Descriptor: "Hypertension/genetics" - Searchworks@Jio Institute Digital Library Search Results

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60 results on '"Hypertension/genetics"'

1. Family History of Hypertension: Impact on Blood Pressure, Anthropometric Measurements and Physical Activity Level in Schoolchildren

Author: Tatiana Affornali Tozo, Beatriz Oliveira Pereira, Francisco José de Menezes, Cristianne Morgado Montenegro, Carla Marisa Maia Moreira, Neiva Leite, and Universidade do Minho
Subjects: Educação de qualidade, Heredity/genetics, Anthropometry, Schoolchildren, Blood Pressure, Physical Activity, Obesity, Hypertension/genetics, Ciências Sociais::Ciências da Educação
Abstract: Background: A family history of arterial hypertension (AH), combined with environmental risk factors, is directly related to the development of AH. Objective: To evaluate the frequency of AH, anthropometric indicators and level of physical activity and their association with a family history (FH) of AH in school children. Methods: Cross-sectional study with 118 students, aged between 11 and 17 years, of both sexes. Waist circumference (WC), weight, height, level of physical activity and FH of HA were collected. Body mass index z score (BMI-z) and waist-to-height ratio (WHtR) were calculated. Binary logistic regression model was used to verify the chance risk, with significance p, FCT -Fundação para a Ciência e a Tecnologia(UIDB/00317/2020)
Published: 2022

2. Gut microbial DNA and immune checkpoint gene Vsig4/CRIg are key antagonistic players in healthy aging and age-associated development of hypertension and diabetes

Author: Matthew A. Liu, Shandy Shahabi, Suborno Jati, Kechun Tang, Hong Gao, Zhongmou Jin, Wyatt Miller, Frédéric A. Meunier, Wei Ying, Geert van den Bogaart, Gourisankar Ghosh, Sushil K. Mahata, and Molecular Immunology
Subjects: DNA, Bacterial, Aging, hypertension, Endocrinology, Diabetes and Metabolism, Knockout, Clinical Sciences, Insulin Resistance/genetics, Cardiovascular, Mice, insulin resistance, Inflammation/genetics, Genetics, Diabetes Mellitus, 2.1 Biological and endogenous factors, Animals, Aetiology, pancreastatin, Mice, Knockout, Inflammation, Nutrition and Dietetics, diabetes, Bacterial, catestatin, DNA, Gastrointestinal Microbiome, healthy aging, Hypertension, Chromogranin A, Insulin Resistance, Hypertension/genetics
Abstract: AimsAging is associated with the development of insulin resistance and hypertension which may stem from inflammation induced by accumulation of toxic bacterial DNA crossing the gut barrier. The aim of this study was to identify factors counter-regulating these processes. Taking advantage of the Chromogranin A (CgA) knockout (CgA-KO) mouse as a model for healthy aging, we have identified Vsig4 (V-set and immunoglobulin domain containing 4) as the critical checkpoint gene in offsetting age-associated hypertension and diabetes.Methods and ResultsThe CgA-KO mice display two opposite aging phenotypes: hypertension but heightened insulin sensitivity at young age, whereas the blood pressure normalizes at older age and insulin sensitivity further improves. In comparison, aging WT mice gradually lost glucose tolerance and insulin sensitivity and developed hypertension. The gut barrier, compromised in aging WT mice, was preserved in CgA KO mice leading to major 35-fold protection against bacterial DNA-induced inflammation. Similarly, RNA sequencing showed increased expression of the Vsig4 gene (which removes bacterial DNA) in the liver of 2-yr-old CgA-KO mice, which may account for the very low accumulation of microbial DNA in the heart. The reversal of hypertension in aging CgA-KO mice likely stems from (i) low accumulation of microbial DNA, (ii) decreased spillover of norepinephrine in the heart and kidneys, and (iii) reduced inflammation.ConclusionWe conclude that healthy aging relies on protection from bacterial DNA and the consequent low inflammation afforded by CgA-KO. Vsig4 also plays a crucial role in “healthy aging” by counteracting age-associated insulin resistance and hypertension.
Published: 2022

3. Family history: an opportunity for early interventions and improved control of hypertension, obesity and diabetes

Author: van der Sande Marianne A.B., Walraven Gijs E.L., Milligan Paul J.M., Banya Winston A.S., Ceesay Sana M., Nyan Ousman A., and McAdam Keith P.W.J.
Subjects: Hypertension/genetics, Obesity/genetics, Diabetes mellitus/genetics, Cerebrovascular accident/genetics, Genetic predisposición to disease, Risk assessment, Cross-sectional studies, Ghana, Public aspects of medicine, RA1-1270
Abstract: OBJECTIVE: To examine whether a family history of high-risk groups for major noncommunicable diseases (NCDs) was a significant risk factor for these conditions among family members in a study population in the Gambia, where strong community and family coherence are important determinants that have to be taken into consideration in promoting lifestyle changes. METHODS: We questioned 5389 adults as to any first-degree family history of major noncommunicable diseases (hypertension, obesity, diabetes and stroke), and measured their blood pressure (BP) and body mass index (BMI). Total blood cholesterol, triglyceride, uric acid, and creatinine concentrations were measured in a stratified subsample, as well as blood glucose (2 hours after ingesting 75 g glucose) in persons aged 35 years. FINDINGS: A significant number of subjects reported a family history of hypertension (8.0%), obesity (5.4%), diabetes (3.3%) and stroke (1.4%), with 14.6% of participants reporting any of these NCDs. Subjects with a family history of hypertension had a higher diastolic BP and BMI, higher cholesterol and uric acid concentrations, and an increased risk of obesity. Those with a family history of obesity had a higher BMI and were at increased risk of obesity. Individuals with a family history of diabetes had a higher BMI and higher concentrations of glucose, cholesterol, triglycerides and uric acid, and their risk of obesity and diabetes was increased. Subjects with a family history of stroke had a higher BMI, as well as higher cholesterol, triglyceride and uric acid concentrations. CONCLUSION: A family history of hypertension, obesity, diabetes, or stroke was a significant risk factor for obesity and hyperlipidaemia. With increase of age, more pathological manifestations can develop in this high-risk group. Health professionals should therefore utilize every opportunity to include direct family members in health education.
Published: 2001

4. Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci

Author: Yongmei Liu, Tuomas O. Kilpeläinen, Kenneth Rice, Ching-Ti Liu, Jin-Fang Chai, Donna K. Arnett, Dhananjay Vaidya, Nicholette D. Palmer, Lili Milani, Yuri Milaneschi, Leo-Pekka Lyytikäinen, Colleen M. Sitlani, Richard S. Cooper, Gudny Eiriksdottir, Daniel Levy, Jerome I. Rotter, Lihua Wang, Sven Bergmann, Yih Chung Tham, Thomas Meitinger, Lynne E. Wagenknecht, Virginia Fisher, Babatunde L. Salako, Vilmundur Gudnason, Bamidele O. Tayo, Caizheng Yu, Barry I. Freedman, Muhammad Riaz, Kaare Christensen, Ulrich Broeckel, W. James Gauderman, Massimiliano Cocca, Eric Boerwinkle, Meian He, Rob M. van Dam, M. Arfan Ikram, Lisa de las Fuentes, Jiang He, Aldi T. Kraja, Nancy L. Pedersen, Albert V. Smith, Woon-Puay Koh, Bernardo L. Horta, He Gao, Traci M. Bartz, Mike A. Nalls, Federica Laguzzi, Raymond Noordam, Paul M. Ridker, Tien Yin Wong, Patricia B. Munroe, Paul S. de Vries, Adolfo Correa, Maris Alver, Dan E. Arking, Colin A. McKenzie, John M. Starr, Chi Charles Gu, Dongfeng Gu, Stefan Weiss, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Jill M. Norris, Patrik K. E. Magnusson, Tamar Sofer, Ioanna Ntalla, Xiuqing Guo, Paul Elliott, Lawrence F. Bielak, Konstantin Strauch, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Ilja M. Nolte, Steven C. Hunt, Mario Sims, Giorgia Girotto, Chuan Gao, Pamela J. Schreiner, Philippe Froguel, Archie Campbell, Xiao-Ou Shu, Claude Bouchard, Kurt Lohman, David R. Weir, José Eduardo Krieger, Yii-Der Ida Chen, Rainer Rauramaa, Walter Palmas, Cornelia M. van Duijn, James M. Shikany, Michael M. Province, Jennifer A. Smith, Wei Zheng, Xiaofeng Zhu, Jianjun Liu, Ozren Polasek, Alexandre C. Pereira, Diane M. Becker, Kari E. North, Salman M. Tajuddin, Deng Xuan, Leslie J. Raffel, Jie Yao, Astrid Petersmann, Ervin F. Fox, Mark J. Caulfield, Daniel I. Chasman, Jasmin Divers, Claudia P. Cabrera, Rico Rueedi, M. Yldau van der Ende, Carl D. Langefeld, Mika Kähönen, Terrence Forrester, Tangchun Wu, Harold Snieder, Caroline Hayward, Tamara B. Harris, Fang-Chi Hsu, Helen R. Warren, Brenda W.J.H. Penninx, Chiea Chuen Khor, Ruifang Li-Gao, Changwei Li, Sami Heikkinen, Jeffrey R. O'Connell, Christian Gieger, Michele K. Evans, Ching-Yu Cheng, Jingjing Liang, Stephen B. Kritchevsky, Gregory L. Burke, Donald W. Bowden, Alexander Teumer, Marcus Dörr, Alanna C. Morrison, Jian-Min Yuan, Annette Peters, Dennis O. Mook-Kanamori, Pedro Marques-Vidal, Pirjo Komulainen, Lisa R. Yanek, Melanie Waldenberger, Alisa K. Manning, Charles N. Rotimi, Chew-Kiat Heng, Tõnu Esko, Franco Giulianini, Miao Li Chee, Treva Rice, David J. Porteous, Yechiel Friedlander, Bing Yu, Myriam Fornage, Karin Leander, Dina Vojinovic, Sharon L.R. Kardia, Xiaoyin Li, Najaf Amin, Karen Schwander, Thomas T. Perls, Oscar Leonel Rueda-Ochoa, Erin B. Ware, Ya Xing Wang, Sandosh Padmanabhan, H. Janaka de Silva, André G. Uitterlinden, Rajkumar Dorajoo, Bruna Gigante, Jennifer A. Brody, Paolo Gasparini, Maryam Kavousi, Wanqing Wen, Stephen Sidney, Alan B. Zonderman, Michael R. Brown, Tuomo Rankinen, Timo A. Lakka, Yun Ju Sung, Alaitz Poveda, Bruce M. Psaty, Terho Lehtimäki, Tanika N. Kelly, Igor Rudan, Brigitte Kühnel, Christopher P. Nelson, John M. C. Connell, Mickaël Canouil, Niek Verweij, Thomas W. Winkler, Ian J. Deary, Marco Brumat, Yize Li, Fumihiko Takeuchi, Wei Zhao, Andres Metspalu, Marguerite R. Irvin, David C. Liewald, Pim van der Harst, Hugues Aschard, Candace M. Kammerer, Melissa A. Richard, Adesola Ogunniyi, Wen Bin Wei, Morris A. Swertz, Fernando Pires Hartwig, Dabeeru C. Rao, Reedik Mägi, Solomon K. Musani, Mathilde Boissel, Jonathan Marten, Nilesh J. Samani, Amy R. Bentley, Sarah E. Harris, Charumathi Sabanayagam, Mary F. Feitosa, Jost B. Jonas, Andrea R. V. R. Horimoto, Paul W. Franks, E. Shyong Tai, Medical Research Council (MRC), de las Fuentes, L., Sung, Y. J., Noordam, R., Winkler, T., Feitosa, M. F., Schwander, K., Bentley, A. R., Brown, M. R., Guo, X., Manning, A., Chasman, D. I., Aschard, H., Bartz, T. M., Bielak, L. F., Campbell, A., Cheng, C. -Y., Dorajoo, R., Hartwig, F. P., Horimoto, A. R. V. R., Li, C., Li-Gao, R., Liu, Y., Marten, J., Musani, S. K., Ntalla, I., Rankinen, T., Richard, M., Sim, X., Smith, A. V., Tajuddin, S. M., Tayo, B. O., Vojinovic, D., Warren, H. R., Xuan, D., Alver, M., Boissel, M., Chai, J. -F., Chen, X., Christensen, K., Divers, J., Evangelou, E., Gao, C., Girotto, G., Harris, S. E., He, M., Hsu, F. -C., Kuhnel, B., Laguzzi, F., Li, X., Lyytikainen, L. -P., Nolte, I. M., Poveda, A., Rauramaa, R., Riaz, M., Rueedi, R., Shu, X. -O., Snieder, H., Sofer, T., Takeuchi, F., Verweij, N., Ware, E. B., Weiss, S., Yanek, L. R., Amin, N., Arking, D. E., Arnett, D. K., Bergmann, S., Boerwinkle, E., Brody, J. A., Broeckel, U., Brumat, M., Burke, G., Cabrera, C. P., Canouil, M., Chee, M. L., Chen, Y. -D. I., Cocca, M., Connell, J., de Silva, H. J., de Vries, P. S., Eiriksdottir, G., Faul, J. D., Fisher, V., Forrester, T., Fox, E. F., Friedlander, Y., Gao, H., Gigante, B., Giulianini, F., Gu, C. C., Gu, D., Harris, T. B., He, J., Heikkinen, S., Heng, C. -K., Hunt, S., Ikram, M. A., Irvin, M. R., Kahonen, M., Kavousi, M., Khor, C. C., Kilpelainen, T. O., Koh, W. -P., Komulainen, P., Kraja, A. T., Krieger, J. E., Langefeld, C. D., Li, Y., Liang, J., Liewald, D. C. M., Liu, C. -T., Liu, J., Lohman, K. K., Magi, R., Mckenzie, C. A., Meitinger, T., Metspalu, A., Milaneschi, Y., Milani, L., Mook-Kanamori, D. O., Nalls, M. A., Nelson, C. P., Norris, J. M., O'Connell, J., Ogunniyi, A., Padmanabhan, S., Palmer, N. D., Pedersen, N. L., Perls, T., Peters, A., Petersmann, A., Peyser, P. A., Polasek, O., Porteous, D. J., Raffel, L. J., Rice, T. K., Rotter, J. I., Rudan, I., Rueda-Ochoa, O. -L., Sabanayagam, C., Salako, B. L., Schreiner, P. J., Shikany, J. M., Sidney, S. S., Sims, M., Sitlani, C. M., Smith, J. A., Starr, J. M., Strauch, K., Swertz, M. A., Teumer, A., Tham, Y. C., Uitterlinden, A. G., Vaidya, D., van der Ende, M. Y., Waldenberger, M., Wang, L., Wang, Y. -X., Wei, W. -B., Weir, D. R., Wen, W., Yao, J., Yu, B., Yu, C., Yuan, J. -M., Zhao, W., Zonderman, A. B., Becker, D. M., Bowden, D. W., Deary, I. J., Dorr, M., Esko, T., Freedman, B. I., Froguel, P., Gasparini, P., Gieger, C., Jonas, J. B., Kammerer, C. M., Kato, N., Lakka, T. A., Leander, K., Lehtimaki, T., Magnusson, P. K. E., Marques-Vidal, P., Penninx, B. W. J. H., Samani, N. J., van der Harst, P., Wagenknecht, L. E., Wu, T., Zheng, W., Zhu, X., Bouchard, C., Cooper, R. S., Correa, A., Evans, M. K., Gudnason, V., Hayward, C., Horta, B. L., Kelly, T. N., Kritchevsky, S. B., Levy, D., Palmas, W. R., Pereira, A. C., Province, M. M., Psaty, B. M., Ridker, P. M., Rotimi, C. N., Tai, E. S., van Dam, R. M., van Duijn, C. M., Wong, T. Y., Rice, K., Gauderman, W. J., Morrison, A. C., North, K. E., Kardia, S. L. R., Caulfield, M. J., Elliott, P., Munroe, P. B., Franks, P. W., Rao, D. C., Fornage, M., Washington University in Saint Louis (WUSTL), Leiden University Medical Center (LUMC), University of Regensburg, Washington University School of Medicine in St. Louis, National Institutes of Health [Bethesda] (NIH), Harbor UCLA Medical Center [Torrance, Ca.], Massachusetts General Hospital [Boston], Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard School of Public Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), The University of Texas Health Science Center at Houston (UTHealth), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Digital Health, Universiteit Leiden, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Lifelines Cohort Study, Epidemiology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Cardiovascular Centre (CVC)
Subjects: 0301 basic medicine, CORONARY-HEART-DISEASE, SOCIOECONOMIC-STATUS, RISK-FACTORS, CARDIOVASCULAR-DISEASE, ESSENTIAL-HYPERTENSION, C825T POLYMORPHISM, SOCIAL-CLASS, ASSOCIATION, EXPRESSION, VARIANTS, Blood Pressure, Genome, 0302 clinical medicine, 11 Medical and Health Sciences, Genetics, Psychiatry, [STAT.AP]Statistics [stat]/Applications [stat.AP], 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Meta-analysis, Hypertension, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, GNB3, Biochemistry & Molecular Biology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Lifelines Cohort Study, SDG 3 - Good Health and Well-being, Humans, Risk factor, Molecular Biology, Gene, Science & Technology, Neurosciences, Epistasis, Genetic, 06 Biological Sciences, Genetic architecture, Educational attainment, 030104 developmental biology, Blood pressure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurosciences & Neurology, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Blood Pressure/genetics, Genome-Wide Association Study, Hypertension/genetics, 030217 neurology & neurosurgery
Abstract: Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10 -8 ). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
Published: 2020
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5. Role of the renin-angiotensin system in kidney development and programming of adult blood pressure

Author: Lucas Ferreira de Almeida, Boye L. Jensen, Signe Skou Tofteng, and Kirsten Madsen
Subjects: 0301 basic medicine, Vascular Endothelial Growth Factor A, medicine.medical_specialty, kidney, Angiotensins, hypertension, Blood Pressure, 030204 cardiovascular system & hematology, Kidney, Renin/metabolism, Vascular Endothelial Growth Factor A/genetics, Renin-Angiotensin System, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Renin–angiotensin system, Renin, medicine, Humans, Animals, development, Kidney/growth & development, Angiotensin II receptor type 1, biology, business.industry, Angiotensin-converting enzyme, Angiotensins/metabolism, General Medicine, Angiotensin II, Vascular endothelial growth factor, 030104 developmental biology, Blood pressure, Endocrinology, medicine.anatomical_structure, chemistry, renin, Renal blood flow, Hypertension, biology.protein, business, Hypertension/genetics
Abstract: Adverse events during fetal life such as insufficient protein intake or elevated transfer of glucocorticoid to the fetus may impact cardiovascular and metabolic health later in adult life and are associated with increased incidence of type 2 diabetes, ischemic heart disease and hypertension. Several adverse factors converge and suppress the fetal renin–angiotensin–aldosterone system (RAAS). The aim of this review is to summarize data on the significance of RAAS for kidney development and adult hypertension. Genetic inactivation of RAAS in rodents at any step from angiotensinogen to angiotensin II (ANGII) type 1 receptor (AT1) receptors or pharmacologic inhibition leads to complex developmental injury to the kidneys that has also been observed in human case reports. Deletion of the ‘protective’ arm of RAAS, angiotensin converting enzyme (ACE) 2 (ACE-2) and G-protein coupled receptor for Angiotensin 1–7 (Mas) receptor does not reproduce the AT1 phenotype. The changes comprise fewer glomeruli, thinner cortex, dilated tubules, thicker arterioles and arteries, lack of vascular bundles, papillary atrophy, shorter capillary length and volume in cortex and medulla. Altered activity of systemic and local regulators of fetal-perinatal RAAS such as vitamin D and cyclooxygenase (COX)/prostaglandins are associated with similar injuries. ANGII–AT1 interaction drives podocyte and epithelial cell formation of vascular growth factors, notably vascular endothelial growth factor (VEGF) and angiopoietins (Angpts), which support late stages of glomerular and cortical capillary growth and medullary vascular bundle formation and patterning. RAAS-induced injury is associated with lower glomerular filtration rate (GFR), lower renal plasma flow, kidney fibrosis, up-regulation of sodium transporters, impaired sodium excretion and salt-sensitive hypertension. The renal component and salt sensitivity of programmed hypertension may impact dietary counseling and choice of pharmacological intervention to treat hypertension.
Published: 2020
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6. Human formyl peptide receptor 1 C32T SNP interacts with age and is associated with blood pressure levels

Author: El Shamieh, Said, Herbeth, Bernard, Azimi-Nezhad, Mohsen, Benachour, Hamanou, Masson, Christine, and Visvikis-Siest, Sophie
Subjects: *PEPTIDE drugs, *HYPERTENSION, *PATHOLOGICAL physiology, *INFLAMMATION, *ADULTS, *AGE factors in disease, *FRENCH people
Abstract: Abstract: Background: Human formyl peptide receptor 1 (FPR1) mediates inflammatory responses, recognized as important participants in the physiopathology of hypertension. Similarly, FPR1 C32T SNP is associated with inflammation and BP related pathways. Therefore, the relationship between FPR1 C32T SNP, BP and hypertension needs to be investigated. Method: 1012 French middle-aged adults including 491 healthy individuals (5years follow-up, T+0 and T+5) and 521 hypertensive individuals were PCR-RFLP genotyped for FPR1 C32T SNP (rs5030878). Results: At entrance, there was no significant association between FPR1 C32T SNP and blood pressure (BP) in healthy individuals. However, 5years later, significant associations were found for DBP, SBP (p < 0.001 and p=0.009 respectively) and for their 5years changes (Δ) (p=0.025 and p=0.027 for DBP and SBP respectively). Significant interactions between FPR1 C32T SNP and age on DBP, SBP, ΔDBP and ΔSBP were found (p=0.014, 0.008, 0.015 and 0.015 respectively). Consequently, stronger increase in BP was reported among healthy individuals aged less than 45years. When normotensive individuals were compared to hypertensives ones, similar FPR1 C32T genotypes and allele frequency distributions were found. Conclusion: FPR1 C32T SNP interacts with age, is associated with higher and a 5years increase of BP levels in healthy individuals aged less than 45years. [Copyright &y& Elsevier]
Published: 2012
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7. Connexin37‐Dependent Mechanisms Selectively Contribute to Modulate Angiotensin II‐Mediated Hypertension

Author: Armin Kurtz, Loïc Le Gal, Charlotte Wagner, Jacques-Antoine Haefliger, Maxime Pellegrin, Lucia Mazzolai, Paolo Meda, and Tania Santoro
Subjects: MAPK/ERK pathway, Male, medicine.medical_specialty, kidney, Myosin Light Chains, Myocytes, Smooth Muscle, Blood Pressure, 030204 cardiovascular system & hematology, angiotensin II, Receptor, Angiotensin, Type 2, Connexins, Muscle, Smooth, Vascular, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, Renin–angiotensin system, Renin, medicine, Animals, Vasoconstrictor Agents, Enzyme Inhibitors, Receptor, Extracellular Signal-Regulated MAP Kinases, Protein kinase B, Aorta, 030304 developmental biology, Original Research, Mice, Knockout, 0303 health sciences, Kidney, business.industry, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Endothelial Cells, Angiotensin II, smooth muscle cells, Disease Models, Animal, Angiotensin II/pharmacology, Aorta/cytology, Aorta/drug effects, Aorta/metabolism, Blood Pressure/drug effects, Blood Pressure/genetics, Connexins/genetics, Endothelial Cells/metabolism, Enzyme Inhibitors/pharmacology, Extracellular Signal-Regulated MAP Kinases/metabolism, Hypertension/genetics, Hypertension/metabolism, Muscle, Smooth, Vascular/cytology, Myocytes, Smooth Muscle/metabolism, Myosin Light Chains/metabolism, NG-Nitroarginine Methyl Ester/pharmacology, Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics, Proto-Oncogene Proteins c-akt/metabolism, Receptor, Angiotensin, Type 2/metabolism, Renin/metabolism, Vasoconstrictor Agents/pharmacology, aorta, connexins, endothelial cells, hypertension, Endocrinology, medicine.anatomical_structure, Blood pressure, NG-Nitroarginine Methyl Ester, High Blood Pressure, Hypertension, Phosphorylation, Cardiology and Cardiovascular Medicine, business, Proto-Oncogene Proteins c-akt
Abstract: Background Gap junction channels made of Connexin37 (Cx37) are expressed by aortic endothelial and smooth muscle cells of hypertensive mice, as well as by the renin‐secreting cells of kidneys. Methods and Results To decipher whether Cx37 has any role in hypertension, angiotensin II (Ang II ) was infused in normotensive wild‐type and Cx37‐deficient mice (Cx37−/−). After 2 to 4 weeks, the resulting increase in blood pressure was lower in Cx37−/− than in wild‐type mice, suggesting an alteration in the Ang II response. To investigate this possibility, mice were submitted to a 2‐kidney, 1‐clip procedure, a renin‐dependent model of hypertension. Two weeks after this clipping, Cx37−/− mice were less hypertensive than wild‐type mice and, 2 weeks later, their blood pressure had returned to control values, in spite of abnormally high plasma renin levels. In contrast, Cx37−/− and wild‐type mice that received N ‐nitro‐ l ‐arginine‐methyl‐ester, a renin‐independent model of hypertension, featured a similar and sustained increase in blood pressure. The data indicate that loss of Cx37 selectively altered the Ang II ‐dependent pathways. Consistent with this conclusion, aortas of Cx37−/− mice featured an increased basal expression of the Ang II type 2 receptors ( AT 2R), and increased transcripts levels of downstream signaling proteins, such as Cnksr1 and Ptpn6 ( SHP ‐1). Accordingly, the response of Cx37−/− mice aortas to an ex vivo Ang II exposure was altered, since phosphorylation levels of several proteins of the Ang II pathway ( MLC 2, ERK , and AKT ) remained unchanged. Conclusions These findings provide evidence that Cx37 selectively influences Ang II signaling, mostly via a modulation of the expression of the Ang II type 2 receptor.
Published: 2019

8. Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

Author: Paul M. Ridker, Han Chen, Nathan O. Stitziel, Joshua C. Bis, Charles Kooperberg, Stephan B. Felix, Digna R. Velez Edwards, Cristian Pattaro, Alanna C. Morrison, Praveen Surendran, Adolfo Correa, Nilesh J. Samani, Johanna Jakobsdottir, Gulum Kosova, Fotios Drenos, Heribert Schunkert, Li-An Lin, Bruce M. Psaty, Vilmundur Gudnason, Jerome I. Rotter, Panos Deloukas, Uwe Völker, Ayush Giri, George J. Papanicolaou, Todd L. Edwards, E. Warwick Daw, André G. Uitterlinden, Eric Boerwinkle, Elias Salfati, Chunyu Liu, Tianxiao Huan, Eric Kim, Daniel Levy, Krystal S Tsosie, Albert V. Smith, Martin G. Larson, Georg Ehret, Cornelia M. van Duijn, Christopher J. O'Donnell, Stefan Weiss, Kiang Liu, Omri Gottesman, Wei Zhao, Claude Bouchard, Walter Palmas, Santhi K. Ganesh, Alexander P. Reiner, Kent D. Taylor, Mathias Gorski, Megan L. Grove, Wayne H-H Sheu, Wen-Jane Lee, Jennifer A. Brody, James P. Cook, Jacques E. Rossouw, Oscar H. Franco, Yongmei Liu, Erwin P. Bottinger, Christopher Newton-Cheh, Lisa W. Martin, Jie Yao, Paul L. Auer, Aldi T. Kraja, Kenneth Rice, Marcus Dörr, Hao Mei, Myriam Fornage, Najaf Amin, Lenore J. Launer, Jessica D. Faul, Arend Voorman, Shih-Jen Hwang, Nora Franceschini, Ingrid B. Borecki, Aravinda Chakravarti, Yingchang Lu, Yii-Der Ida Chen, Tamara B. Harris, Audrey Y. Chu, Sharon L.R. Kardia, Xiuqing Guo, David R. Weir, Rainer Rettig, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Leslie J. Raffel, Christian Fuchsberger, Daniel I. Chasman, Jeanette M. Stafford, Man Li, I-Te Lee, Henry Völzke, Ruth J. F. Loos, Jennifer A. Smith, Epidemiology, and Internal Medicine
Subjects: 0301 basic medicine, Blood Pressure/genetics, Genotype, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Genetics, Missense mutation, Humans, Exome, Polymorphism, Gene, Oligonucleotide Array Sequence Analysis, ddc:616, Genome, Genome, Human, Genetic Variation, Single Nucleotide, 030104 developmental biology, Blood pressure, Hypertension, Human genome, Hypertension/genetics, Human, Genome-Wide Association Study
Abstract: Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Published: 2016
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9. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

Author: Olle Melander, Niek Verweij, Uwe Völker, Morris A. Swertz, Seppo Koskinen, David Conen, Lars Lind, Rossella Sorice, Philippe Amouyel, Andres Metspalu, David J. Stott, Marty Larson, Francis S. Collins, Ozren Polasek, Paul F. O'Reilly, Albertine J. Oldehinkel, Evangelos Evangelou, Pekka Jousilahti, Michela Traglia, Tineka Blake, John Attia, Bruce M. Psaty, Massimo Mangino, Alison Pattie, Marco Brumat, Dorret I. Boomsma, Harry Campbell, Daniel I. Chasman, Tõnu Esko, Wei-Yu Lin, Rodney J. Scott, Marjo-Riitta Järvelin, Guillaume Paré, Adriana M. Hung, Marina Evangelou, Quang Tri Nguyen, Markus Perola, Kenneth Rice, Yong Qian, Antonietta Robino, Anne U. Jackson, Ian J. Deary, Mika Kähönen, Cristina Menni, Veronique Vitart, Igor Rudan, Ganesh Chauhan, Aravinda Chakravarti, Jennifer E. Huffman, John M. Starr, Anubha Mahajan, Christopher Newton-Cheh, Peter Almgren, Yuri Milaneschi, Jacklyn N. Hellwege, Roby Joehanes, Christopher P. Nelson, Eleftheria Zeggini, Elizabeth G. Holliday, Peter J. van der Most, Annette Peters, Paul M. Ridker, Michael Boehnke, Joris Deelen, Brenda W.J.H. Penninx, Neil Poulter, Renée de Mutsert, Rick Jansen, Fu Liang Ng, Anne-Claire Vergnaud, Ilja M. Nolte, Meixia Ren, Gail Davies, John M. C. Connell, Jian'an Luan, Todd L. Edwards, Benjamin Lehne, K. Witkowska, Lili Milani, Stéphanie Debette, Georgios Ntritsos, Claudia P. Cabrera, Paolo Gasparini, Jouke-Jan Hottenga, Antti-Pekka Sarin, Kelly Cho, Robert A. Scott, Veikko Salomaa, Niki Dimou, David C. Liewald, Pim van der Harst, Teemu J. Niiranen, Denis C. Shields, Leo-Pekka Lyytikäinen, Andrew P. Morris, Murielle Bochud, Helena Schmidt, Bernard Keavney, Christopher Oldmeadow, Ioanna Tzoulaki, Jaakko Tuomilehto, Louise V. Wain, Reedik Mägi, Christian Gieger, Caterina Barbieri, Aki S. Havulinna, Fabiola Del Greco M, Dragana Vuckovic, Alan F. Wright, J. Wouter Jukema, Reinhold Schmidt, Marcus Dörr, Franco Giulianini, Evan Tzanis, Erwin P. Bottinger, David Mosen-Ansorena, Ruth J. F. Loos, A. Mesut Erzurumluoglu, Teresa Nutile, Alice Stanton, Jun Ding, Yingchang Lu, Roberto Elosua, Walter Palmas, James F. Wilson, Edith Hofer, Giorgia Girotto, Bram P. Prins, Anna Morgan, Anuj Goel, Edward G. Lakatta, Alex S. F. Doney, Najaf Amin, Lenore J. Launer, Siim Sõber, Nicholas J. Wareham, Adam S. Butterworth, Ilaria Gandin, Xiuqing Guo, Kent D. Taylor, Andrew D. Morris, Paul Knekt, Cinzia Sala, Peter P. Pramstaller, Joshua C. Bis, Archie Campbell, Raha Pazoki, Hugh Watkins, Csaba P. Kovesdy, Yan V. Sun, Lynda M. Rose, Jaspal S. Kooner, Maciej Tomaszewski, Massimiliano Cocca, Claudia Langenberg, Gonneke Willemsen, Eco J. C. de Geus, Peter W.F. Wilson, Ahmad Vaez, Albert Hofman, Kristin L. Ayers, Sara M. Willems, Germaine C. Verwoert, Christophe Tzourio, Martin Farrall, Albert V. Smith, Joanna M. M. Howson, Daniela Toniolo, Digna R. Velez Edwards, Antti Jula, Stefan Enroth, Ruifang Li-Gao, Nabi Shah, Weihua Zhang, Paul Elliott, Dennis O. Mook-Kanamori, Tatijana Zemunik, Shih-Jen Hwang, Helen R. Warren, Peter J. Munson, He Gao, Ivana Kolcic, Peter S. Braund, Tamara B. Harris, Raymond Noordam, Stella Trompet, Markku Laakso, Peter K. Joshi, Zoltán Kutalik, Sébastien Thériault, Åsa Johansson, Rainer Rettig, Sarah H. Wild, Patricia B. Munroe, John Danesh, Anders Hamsten, Mark J. Caulfield, Gonçalo R. Abecasis, Praveen Surendran, Peter S. Sever, David S. Siscovick, Terho Lehtimäki, Priyanka Nandakumar, Aarno Palotie, Muralidharan Sargurupremraj, Chiara Batini, Nick Shrine, Harold Snieder, Cumhur Y Demirkale, Teresa Ferreira, André G. Uitterlinden, Sekar Kathiresan, Mattias Frånberg, Lorna M. Lopez, J. Michael Gaziano, Cornelia M. van Duijn, Maris Laan, Samuli Ripatti, John C. Chambers, Martin H. de Borst, Johan Sundström, Alan J. Gow, Caroline Hayward, Oscar H. Franco, Yongmei Liu, Sandosh Padmanabhan, Ibrahim Karaman, Georg Ehret, Cecilia M. Lindgren, Mike A. Nalls, Chrysovalanto Mamasoula, Daniela Ruggiero, Erik Ingelsson, Colin N. A. Palmer, Alan James, Elin Org, Kati Kristiansson, Alexander Teumer, Ulf Gyllensten, Joanne Knight, Vilmantas Giedraitis, Jerome I. Rotter, Yasaman Saba, Daniel Levy, Li Lin, Janina S. Ried, Michael R. Barnes, Harriëtte Riese, Andrew D. Johnson, David P. Strachan, Martin D. Tobin, Lorenz Risch, Rona J. Strawbridge, Jing Hua Zhao, Vilmundur Gudnason, Borbala Mifsud, Eric Boerwinkle, Catharina A. Hartman, Ben A. Oostra, Dan E. Arking, Andrew A. Hicks, Peter Vollenweider, Thibaud Boutin, Philip S. Tsao, Jie Yao, Ayush Giri, Marina Ciullo, Morris J. Brown, Alanna C. Morrison, Kay-Tee Khaw, Francesco Cucca, Jonathan Marten, Olli T. Raitakari, Christopher J. O'Donnell, Jaume Marrugat, Tim D. Spector, Heather J. Cordell, Nilesh J. Samani, Simon Thom, Sarah E. Harris, UNIVERSITY OF OULU, Commission of the European Communities, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, National Institute for Health Research, British Heart Foundation, Medical Research Council (MRC), UK DRI Ltd, Epidemiology, Internal Medicine, Lee Kong Chian School of Medicine (LKCMedicine), Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Ehret, Georg Benedikt, Lin, Li, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Evangelou, Evangelo, Warren, Helen R, Mosen-Ansorena, David, Mifsud, Borbala, Pazoki, Raha, Gao, He, Ntritsos, Georgio, Dimou, Niki, Cabrera, Claudia P, Karaman, Ibrahim, Ng, Fu Liang, Evangelou, Marina, Witkowska, Katarzyna, Tzanis, Evan, Hellwege, Jacklyn N, Giri, Ayush, Velez Edwards, Digna R, Sun, Yan V, Cho, Kelly, Gaziano, J Michael, Wilson, Peter W F, Tsao, Philip S, Kovesdy, Csaba P, Esko, Tonu, Mägi, Reedik, Milani, Lili, Almgren, Peter, Boutin, Thibaud, Debette, Stéphanie, Ding, Jun, Giulianini, Franco, Holliday, Elizabeth G, Jackson, Anne U, Li-Gao, Ruifang, Lin, Wei-Yu, Luan, Jian'An, Mangino, Massimo, Oldmeadow, Christopher, Prins, Bram Peter, Qian, Yong, Sargurupremraj, Muralidharan, Shah, Nabi, Surendran, Praveen, Thériault, Sébastien, Verweij, Niek, Willems, Sara M, Zhao, Jing-Hua, Amouyel, Philippe, Connell, John, de Mutsert, Renée, Doney, Alex S F, Farrall, Martin, Menni, Cristina, Morris, Andrew D, Noordam, Raymond, Paré, Guillaume, Poulter, Neil R, Shields, Denis C, Stanton, Alice, Thom, Simon, Abecasis, Gonçalo, Amin, Najaf, Arking, Dan E, Ayers, Kristin L, Barbieri, Caterina M, Batini, Chiara, Bis, Joshua C, Blake, Tineka, Bochud, Murielle, Boehnke, Michael, Boerwinkle, Eric, Boomsma, Dorret I, Bottinger, Erwin P, Braund, Peter S, Brumat, Marco, Campbell, Archie, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C, Chauhan, Ganesh, Ciullo, Marina, Cocca, Massimiliano, Collins, Franci, Cordell, Heather J, Davies, Gail, Borst, Martin H de, Geus, Eco J de, Deary, Ian J, Deelen, Jori, Del Greco M, Fabiola, Demirkale, Cumhur Yusuf, Dörr, Marcu, Ehret, Georg B, Elosua, Roberto, Enroth, Stefan, Erzurumluoglu, A Mesut, Ferreira, Teresa, Frånberg, Mattia, Franco, Oscar H, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmanta, Gieger, Christian, Girotto, Giorgia, Goel, Anuj, Gow, Alan J, Gudnason, Vilmundur, Guo, Xiuqing, Gyllensten, Ulf, Hamsten, Ander, Harris, Tamara B, Harris, Sarah E, Hartman, Catharina A, Havulinna, Aki S, Hicks, Andrew A, Hofer, Edith, Hofman, Albert, Hottenga, Jouke-Jan, Huffman, Jennifer E, Hwang, Shih-Jen, Ingelsson, Erik, James, Alan, Jansen, Rick, Jarvelin, Marjo-Riitta, Joehanes, Roby, Johansson, Åsa, Johnson, Andrew D, Joshi, Peter K, Jousilahti, Pekka, Jukema, J Wouter, Jula, Antti, Kähönen, Mika, Kathiresan, Sekar, Keavney, Bernard D, Khaw, Kay-Tee, Knekt, Paul, Knight, Joanne, Kolcic, Ivana, Kooner, Jaspal S, Koskinen, Seppo, Kristiansson, Kati, Kutalik, Zoltan, Laan, Mari, Larson, Marty, Launer, Lenore J, Lehne, Benjamin, Lehtimäki, Terho, Liewald, David C M, Lind, Lar, Lindgren, Cecilia M, Liu, Yongmei, Loos, Ruth J F, Lopez, Lorna M, Lu, Yingchang, Lyytikäinen, Leo-Pekka, Mahajan, Anubha, Mamasoula, Chrysovalanto, Marrugat, Jaume, Marten, Jonathan, Milaneschi, Yuri, Morgan, Anna, Morris, Andrew P, Morrison, Alanna C, Munson, Peter J, Nalls, Mike A, Nandakumar, Priyanka, Nelson, Christopher P, Niiranen, Teemu, Nolte, Ilja M, Nutile, Teresa, Oldehinkel, Albertine J, Oostra, Ben A, O'Reilly, Paul F, Org, Elin, Padmanabhan, Sandosh, Palmas, Walter, Palotie, Aarno, Pattie, Alison, Penninx, Brenda W J H, Perola, Marku, Peters, Annette, Polasek, Ozren, Pramstaller, Peter P, Nguyen, Quang Tri, Raitakari, Olli T, Ren, Meixia, Rettig, Rainer, Rice, Kenneth, Ridker, Paul M, Ried, Janina S, Riese, Harriëtte, Ripatti, Samuli, Robino, Antonietta, Rose, Lynda M, Rotter, Jerome I, Rudan, Igor, Ruggiero, Daniela, Saba, Yasaman, Sala, Cinzia F, Salomaa, Veikko, Samani, Nilesh J, Sarin, Antti-Pekka, Schmidt, Reinhold, Schmidt, Helena, Shrine, Nick, Siscovick, David, Smith, Albert V, Snieder, Harold, Sõber, Siim, Sorice, Rossella, Starr, John M, Stott, David J, Strachan, David P, Strawbridge, Rona J, Sundström, Johan, Swertz, Morris A, Taylor, Kent D, Teumer, Alexander, Tobin, Martin D, Tomaszewski, Maciej, Toniolo, Daniela, Traglia, Michela, Trompet, Stella, Tuomilehto, Jaakko, Tzourio, Christophe, Uitterlinden, André G, Vaez, Ahmad, van der Most, Peter J, van Duijn, Cornelia M, Vergnaud, Anne-Claire, Verwoert, Germaine C, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Vuckovic, Dragana, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Wilson, James F, Wright, Alan F, Yao, Jie, Zemunik, Tatijana, Zhang, Weihua, Attia, John R, Butterworth, Adam S, Chasman, Daniel I, Conen, David, Cucca, Francesco, Danesh, John, Hayward, Caroline, Howson, Joanna M M, Laakso, Markku, Lakatta, Edward G, Langenberg, Claudia, Melander, Olle, Mook-Kanamori, Dennis O, Palmer, Colin N A, Risch, Lorenz, Scott, Robert A, Scott, Rodney J, Sever, Peter, Spector, Tim D, van der Harst, Pim, Wareham, Nicholas J, Zeggini, Eleftheria, Levy, Daniel, Munroe, Patricia B, Newton-Cheh, Christopher, Brown, Morris J, Metspalu, Andre, Hung, Adriana M, O'Donnell, Christopher J, Edwards, Todd L, Psaty, Bruce M, Tzoulaki, Ioanna, Barnes, Michael R, Wain, Louise V, Elliott, Paul, Caulfield, Mark J, Groningen Kidney Center (GKC), Lifestyle Medicine (LM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), VU University medical center, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Digital Health, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, University of Helsinki, Clinicum, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Department of Public Health, Complex Disease Genetics, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Population/methods, Genome Informatics, Blood Pressure, Genome-wide association study, GENOME-WIDE ASSOCIATION, CARDIOVASCULAR-DISEASE RISK, UK BIOBANK, HYPERTENSION, VARIANTS, METAANALYSIS, COMMON, HEALTH, RARE, HYPERALDOSTERONISM, Disease, Bioinformatics, Cardiovascular Diseases/epidemiology/genetics, Risk Factors, 80 and over, GWAS, Cells, Cultured, 11 Medical and Health Sciences, ddc:616, Genetics & Heredity, Aged, 80 and over, Cultured, medicine.diagnostic_test, CARDIOVASCULAR RISK, Genetic analysis, Million Veteran Program, Genetics, Population/methods, Single Nucleotide, Middle Aged, PREVALENCE, 3. Good health, Pulse pressure, VINTAGE, Cardiovascular Diseases, Blood pressure, Medical genetics, Female, Medical Genetics, Life Sciences & Biomedicine, Genetic Testing/methods, Adult, medicine.medical_specialty, Blood Pressure/genetics, Cells, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, Medicine [Science], Genetic Predisposition to Disease, Genetic Testing, Polymorphism, HEALTHY, Life Style, Medicinsk genetik, Aged, Genetic testing, Genetic association, Science & Technology, Cardiovascular Diseases/epidemiology, 06 Biological Sciences, Genetic architecture, Genetics, Population, 030104 developmental biology, Genetic Loci, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Hypertension/genetics, Genome-Wide Association Study, Developmental Biology
Abstract: High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future. NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)
Published: 2018
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10. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

Author: Rico Rueedi, Yuri Milaneschi, Brenda W.J.H. Penninx, Neil Poulter, Karen Schwander, Marco Brumat, Kenneth Rice, Yize Li, Veronique Vitart, Ioanna Ntalla, Michele K. Evans, Jeffrey R. O'Connell, Nilesh J. Samani, Colleen M. Sitlani, W. James Gauderman, Xuan Deng, Paul M. Ridker, Yun J. Sung, Yukihide Momozawa, Archie Campbell, Tin Louie, Nona Sotoodehnia, Yii-Der Ida Chen, Cornelia M. van Duijn, Tanika N. Kelly, Peter S. Sever, André G. Uitterlinden, Brigitte Kühnel, John M. Starr, Lawrence F. Bielak, Christopher P. Nelson, Wanqing Wen, Stephan B. Felix, Stefan Weiss, Daniel Levy, Nicholette D. Palmer, Alisa K. Manning, Salman M. Tajuddin, Jill M. Norris, Marie Loh, M. Abdullah Said, Alena Stančáková, Anuradhani Kasturiratne, John M. C. Connell, Jian'an Luan, Tuomas O. Kilpeläinen, Amy R. Bentley, Stephen Sidney, Alan B. Zonderman, Karin Leander, David J. Porteous, Jianjun Liu, Tin Aung, Charles B. Eaton, Sharon L.R. Kardia, Rajkumar Dorajoo, Stephen Turner, Michael Boehnke, Diane M. Becker, Cora E. Lewis, Ozren Polasek, Mickaël Canouil, Kurt Lohman, Georg Ehret, Sarah E. Harris, Robert A. Scott, Claude Bouchard, Lynne E. Wagenknecht, Mohsen Ghanbari, Stephen B. Kritchevsky, Jin-Fang Chai, Gregory L. Burke, Jiang He, Federica Laguzzi, Michael R. Brown, Walter Palmas, Lili Milani, Thomas T. Perls, Tibor V. Varga, José Eduardo Krieger, Erin B. Ware, Tamara B. Harris, Tomohiro Katsuya, Nicole Schupf, Mika Kähönen, Nana Matoba, Hugues Aschard, Ilaria Gandin, Jennifer A. Smith, Traci M. Bartz, James Scott, Tuomo Rankinen, Yuan Shi, Meian He, Timo A. Lakka, Helen R. Warren, Mike A. Nalls, Kent D. Taylor, Woon-Puay Koh, Ya Xing Wang, Muhammad Riaz, Sandosh Padmanabhan, Mary F. Feitosa, Jost B. Jonas, Paul Elliott, Christian Gieger, Terho Lehtimäki, Kaare Christensen, Maris Alver, Pirjo Komulainen, Pamela J. Schreiner, M. Arfan Ikram, David R. Weir, Charles Kooperberg, Oscar H. Franco, Yongmei Liu, Lisa de las Fuentes, Nancy L. Pedersen, Thomas W. Winkler, Bruna Gigante, Göran Hallmans, Ingrid B. Borecki, Shiow Lin, Ian J. Deary, Wei Zheng, Yajuan Wang, Bernardo L. Horta, Heather M. Stringham, Bruce M. Psaty, Paul W. Franks, Weihua Zhang, Nora Franceschini, Adolfo Correa, Nita G. Forouhi, Xiuqing Guo, Fumihiko Takeuchi, L. Adrienne Cupples, William R. Scott, Zoltán Kutalik, He Gao, Nicholas J. Wareham, E. Shyong Tai, Aravinda Chakravarti, C. Charles Gu, Paolo Gasparini, Albertine J. Oldehinkel, Xueling Sim, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Colin A. McKenzie, Qing Duan, Aldi T. Kraja, Carsten Oliver Schmidt, Bamidele O. Tayo, Xiaofeng Zhu, Thomas Meitinger, Mary K. Wojczynski, Markku Laakso, Mark J. Caulfield, Carl D. Langefeld, Jingzhong Ding, Yechiel Friedlander, Tien Yin Wong, Virginia Fisher, Raymond Noordam, Caizheng Yu, Pim van der Harst, Yik Ying Teo, Ervin R. Fox, Sabanayagam Charumathi, Jonathan Marten, Nicholas Y.Q. Tan, Jerome I. Rotter, Harold Snieder, Karen L. Mohlke, Christine Williams, Olli T. Raitakari, Renée de Mutsert, Lihua Wang, Kathryn Roll, Jingmin Liu, Dongfeng Gu, Wei Zhao, Lynda M. Rose, Michael A. Province, Fernando Pires Hartwig, Rob M. van Dam, Barry I. Freedman, Andres Metspalu, Donald W. Bowden, Andrea R. V. R. Horimoto, Martin Farrall, Frits R. Rosendaal, Rainer Rauramaa, Konstantin Strauch, Albert V. Smith, Yanick Hagemeijer, Michiaki Kubo, Ilja M. Nolte, Tõnu Esko, Yih Chung Tham, Cathy C. Laurie, Antonietta Robino, Anne U. Jackson, Chuan Gao, Dabeeru C. Rao, Xiao-Ou Shu, H. Janaka de Silva, Morris J. Brown, Alanna C. Morrison, Peter J. van der Most, Jian-Min Yuan, Melanie Waldenberger, Leslie J. Raffel, Ulrich John, Fang-Chi Hsu, Reedik Mägi, Solomon K. Musani, Chiea Chuen Khor, Mario Sims, Ruben N. Eppinga, Melissa A. Richard, Yoichiro Kamatani, Changwei Li, Qiuyin Cai, Daniel I. Chasman, Mathilde Boissel, Claudia Langenberg, Sami Heikkinen, Jasmin Divers, Saima Afaq, Wen Bin Wei, Jaspal S. Kooner, Terrence Forrester, Hua Tang, Charles N. Rotimi, Anuj Goel, Annette Peters, Tangchun Wu, Dennis O. Mook-Kanamori, Caroline Hayward, Ching-Yu Cheng, Lisa R. Yanek, Ananda R. Wickremasinghe, Chew-Kiat Heng, Myriam Fornage, Dina Vojinovic, Najaf Amin, Lenore J. Launer, Hugh Watkins, Johanna Kuusisto, Jing Hua Zhao, Barbara V. Howard, Vilmundur Gudnason, Ulrich Broeckel, Eric Boerwinkle, Saskia P. Hagenaars, Dan E. Arking, Peter Vollenweider, Alexandre C. Pereira, Jie Yao, Makoto Hirata, Patricia B. Munroe, Patricia A. Peyser, Jessica D. Faul, Xu Chen, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Marzyeh Amini, Benjamin Lehne, Epidemiology, Erasmus MC other, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), School of Health Sciences (UI), Heilbrigðisvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI), Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), University of Regensburg, Queen Mary University of London (QMUL), Harbor UCLA Medical Center [Torrance, Ca.], Department of Epidemiology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, Northwestern Polytechnical University [Xi'an] (NPU), Centre for Molecular Epidemiology, National University of Singapore (NUS), Harvard School of Public Health, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), National Institutes of Health [Bethesda] (NIH), The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., AGES (Age Gene/Environment Susceptibility Reykjavik Study) is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC (Atherosclerosis Risk in Communities): The authors thank the staff and participants of the ARIC study for their important contributions. CARDIA (Coronary Artery Risk Development in Young Adults): This manuscript has been reviewed and approved by CARDIA for scientific content. CHS (Cardiovascular Health Study): A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. IGMM (Institute of Genetics and Molecular Medicine): CROATIA-Korcula: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools and the Croatian Institute for Public Health. We would like to acknowledge the invaluable contributions of the recruitment team in Korcula, the administrative teams in Croatia and Edinburgh and the participants. The SNP genotyping for the CROATIA-Korcula cohort was performed in Helmholtz Zentrum München, Neuherberg, Germany. CROATIA-Vis: We would like to acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. GS:SFHS: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland. ERF (Erasmus Rucphen Family study): We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work, P. Snijders for his help in data collection and E.M. van Leeuwen for genetic imputation. GENOA (Genetic Epidemiology Network of Arteriopathy): Genotyping was performed at the Mayo Clinic (Stephen T. Turner, MD, Mariza de Andrade PhD, Julie Cunningham, PhD). We thank Eric Boerwinkle, PhD and Megan L. Grove from the Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, Texas, USA for their help with genotyping. We would also like to thank the families that participated in the GENOA study. HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span): Data analyses for the HANDLS study utilized the high-performance computational resources of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD. http://hpc.nih.gov HUFS (Howard University Family Study): We thank the participants of the study. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health. HyperGEN (Hypertension Genetic Epidemiology Network): The study involves: University of Utah: (Network Coordinating Center, Field Center, and Molecular Genetics Lab), Univ. of Alabama at Birmingham: (Field Center and Echo Coordinating and Analysis Center), Medical College of Wisconsin: (Echo Genotyping Lab), Boston University: (Field Center), University of Minnesota: (Field Center and Biochemistry Lab), University of North Carolina: (Field Center), Washington University: (Data Coordinating Center), Weil Cornell Medical College: (Echo Reading Center), National Heart, Lung, & Blood Institute. For a complete list of HyperGEN Investigators: http://www.biostat.wustl.edu/hypergen/Acknowledge.html JHS (Jackson Heart Study): The authors wish to thank the staffs and participants of the JHS. MESA (Multi-Ethnic Study of Atherosclerosis): MESA and the MESA SHARe project are conducted in collaboration with MESA investigators. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. NEO (The Netherlands Epidemiology of Obesity study): The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Petra Noordijk, Pat van Beelen and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. RS (Rotterdam Study) was funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters and Carolina Medina-Gomez for their help in creating the GWAS database, and Karol Estrada, Yurii Aulchenko and Carolina Medina-Gomez for the creation and analysis of imputed data. WHI (Women’s Health Initiative): The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf Replication: AA-DHS (African American Diabetes Heart Study): The investigators acknowledge the cooperation of our Diabetes Heart Study (DHS) and AA-DHS participants. ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial): We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular, we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome chip array. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. BBJ (Biobank Japan Project): We thank all the participants, medical coordinators of the cooperating hospitals for collecting samples and clinical information in the project. BRIGHT (British Genetics of Hypertension): The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. P.B.M, M.J.C and H.R.W wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Centre at Barts and Queen Mary University of London, UK. CoLaus (Cohorte Lausannoise Study): The authors would like to thank all the people who participated in the recruitment of the participants, data collection and validation, particularly Nicole Bonvin, Yolande Barreau, Mathieu Firmann, François Bastardot, Julien Vaucher, Panagiotis Antiochos and Cédric Gubelmann. DESIR (Data from an Epidemiological Study on the Insulin Resistance): The DESIR Study Group is composed of Inserm-U1018 (Paris: B. Balkau, P. Ducimetière, E. Eschwège), Inserm-U367 (Paris: F. Alhenc-Gelas), CHU d’Angers (A. Girault), Bichat Hospital (Paris: F. Fumeron, M. Marre, R. Roussel), CHU de Rennes (F. Bonnet), CNRS UMR-8199 (Lille: A. Bonnefond, P. Froguel), Medical Examination Services (Alençon, Angers, Blois, Caen, Chartres, Chateauroux, Cholet, LeMans, Orléans and Tours), Research Institute for General Medicine (J. Cogneau), the general practitioners of the region and the Cross- Regional Institute for Health (C. Born, E. Caces, M. Cailleau, N. Copin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol). DHS (Diabetes Heart Study): The authors thank the investigators, staff, and participants of the DHS for their valuable contributions. EGCUT Estonian Genome Center—University of Tartu (Estonian Biobank): Data analyzes were carried out in part in the High Performance Computing Center of University of Tartu. EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk: We thank all EPIC participants and staff for their contribution to the study. FENLAND (The Fenland Study): We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for assistance with recruitment. We thank the Fenland Study Investigators, Fenland Study Co-ordination team and the Epidemiology Field, Data and Laboratory teams. We further acknowledge support from the Medical research council (MC_UU_12015/1). GeneSTAR (Genetic Studies of Atherosclerosis Risk): We are very grateful to all of our participants for their long-term involvement. GLACIER (Gene x Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk): We thank the participants, health professionals and data managers involved in the Västerbottens Intervention Project. We are also grateful to the staff of the Northern Sweden Biobank for preparing materials and to K Enqvist and T Johansson (Västerbottens County Council, Umeå, Sweden) for DNA preparation. HCHS/SOL (Hispanic Community Health Study/Study of Latinos): We thank the participants and staff of the HCHS/SOL study for their contributions to this study. HRS (Health & Retirement Study): Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the Genetics Coordinating Center at the University of Washington. HyperGEN-AXIOM (Hypertension Genetic Epidemiology Network—Axiom Chip GWAS): We thank the study investigators, staff and participants for their value contributions. INGI (Italian Network Genetic Isolate): We thank all the inhabitants who participated to the projects. InterAct (The EPIC-InterAct Case-Cohort Study): We thank all EPIC participants and staff for their contribution to the study. IRAS (Insulin Resistance Atherosclerosis Study): The authors thank study investigators, staff, and participants for their valuable contributions. KORA (Cooperative Health Research in the Augsburg Region): We thank all KORA participants and staff for their contribution to the study. LBC1921 (Lothian Birth Cohort 1921): We thank the LBC1921 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LBC1936 (Lothian Birth Cohort 1936): We thank the LBC1936 cohort participants and team members who contributed to these studies. Funding from the Biological Sciences Research Council (BBSRC) and Medical Research Council (MRC) is gratefully acknowledged. LifeLines (Lifelines Cohort Study): The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. The authors wish to acknowledge the services of the Lifelines, the contributing research centers delivering data to Lifelines, and all the study participants. Also, Lifelines acknowledges the contributions from Behrooz Z Alizadeh (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), H Marike Boezen (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Lude Franke (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Pim van der Harst (Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands), Gerjan Navis (Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands), Marianne Rots (Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands), Harold Snieder (Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands), Morris Swertz (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands), Bruce HR Wolffenbuttel (Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands), Cisca Wijmenga (Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands). LLFS (Long Life Family Study): The LLFS would like to thank the participants and research staff who make the study possible. LOLIPOP (London Life Sciences Prospective Population Study): We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. PROCARDIS (Precocious Coronary Artery Disease): The PROCARDIS researchers thank the patients for their selfless participation in this project. RHS (Ragama Health Study): The RHS was supported by the Grant of National Center for Global Health and Medicine (NCGM), Japan. SWHS/SMHS (Shanghai Women's Health Study/ Shanghai Men's Health Study): We thank all the individuals who took part in these studies and all the researchers who have enabled this work to be carried out. TRAILS (TRacking Adolescents’ Individual Lives Survey): TRAILS is a collaborative project involving various departments of the University Medical Center and University of Groningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. We are grateful to all adolescents who participated in this research and to everyone who worked on this project and made it possible. UKB (United Kingdom Biobank, www.ukbiobank.ac.uk): This research has been conducted using the UK Biobank Resource. The UK Biobank data were analyzed from the data set corresponding to UK Biobank access application no. 236, application title 'Genome-wide association study of blood pressure', with Paul Elliott as the PI/applicant. This work was supported by the UK-CMC and the BP working group., InterAct Consortium, Marten, Jonathan [0000-0001-6916-2014], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Forouhi, Nita [0000-0002-5041-248X], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Lee Kong Chian School of Medicine (LKCMedicine), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Feitosa, Mary F., Kraja, Aldi T., Chasman, Daniel I., Sung, Yun J., Winkler, Thomas W., Ntalla, Ioanna, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Marten, Jonathan, Musani, Solomon K., Li, Changwei, Bentley, Amy R., Brown, Michael R., Schwander, Karen, Richard, Melissa A., Noordam, Raymond, Aschard, Hugue, Bartz, Traci M., Bielak, Lawrence F., Dorajoo, Rajkumar, Fisher, Virginia, Hartwig, Fernando P., Horimoto, Andrea R. V. R., Lohman, Kurt K., Manning, Alisa K., Rankinen, Tuomo, Smith, Albert V., Tajuddin, Salman M., Wojczynski, Mary K., Alver, Mari, Boissel, Mathilde, Cai, Qiuyin, Campbell, Archie, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E., He, Meian, Hsu, Fang-Chi, Jackson, Anne U., Kähönen, Mika, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Luan, Jian'An, Matoba, Nana, Nolte, Ilja M., Padmanabhan, Sandosh, Riaz, Muhammad, Rueedi, Rico, Robino, Antonietta, Said, M. Abdullah, Scott, Robert A., Sofer, Tamar, Stančáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O., Van Der Most, Peter J., Varga, Tibor V., Vitart, Veronique, Wang, Yajuan, Ware, Erin B., Warren, Helen R., Weiss, Stefan, Wen, Wanqing, Yanek, Lisa R., Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E., Aung, Tin, Boerwinkle, Eric, Borecki, Ingrid, Broeckel, Ulrich, Brown, Morri, Brumat, Marco, Burke, Gregory L., Canouil, Mickaël, Chakravarti, Aravinda, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M., Correa, Adolfo, De Las Fuentes, Lisa, De Mutsert, Renée, De Silva, H. Janaka, Deng, Xuan, Ding, Jingzhong, Duan, Qing, Eaton, Charles B., Ehret, Georg, Eppinga, Ruben N., Evangelou, Evangelo, Faul, Jessica D., Felix, Stephan B., Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Friedlander, Yechiel, Gandin, Ilaria, Gao, He, Ghanbari, Mohsen, Gigante, Bruna, Gu, C. Charle, Gu, Dongfeng, Hagenaars, Saskia P., Hallmans, Göran, Harris, Tamara B., He, Jiang, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Howard, Barbara V., Ikram, M. Arfan, John, Ulrich, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Krieger, José E., Kritchevsky, Stephen B., Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A., Langefeld, Carl D., Langenberg, Claudia, Launer, Lenore J., Lehne, Benjamin, Lewis, Cora E., Li, Yize, Lin, Shiow, Liu, Jianjun, Liu, Jingmin, Loh, Marie, Louie, Tin, Mägi, Reedik, Mckenzie, Colin A., Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L., Momozawa, Yukihide, Nalls, Mike A., Nelson, Christopher P., Sotoodehnia, Nona, Norris, Jill M., O'Connell, Jeff R., Palmer, Nicholette D., Perls, Thoma, Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Poulter, Neil, Raffel, Leslie J., Raitakari, Olli T., Roll, Kathryn, Rose, Lynda M., Rosendaal, Frits R., Rotter, Jerome I., Schmidt, Carsten O., Schreiner, Pamela J., Schupf, Nicole, Scott, William R., Sever, Peter S., Shi, Yuan, Sidney, Stephen, Sims, Mario, Sitlani, Colleen M., Smith, Jennifer A., Snieder, Harold, Starr, John M., Strauch, Konstantin, Stringham, Heather M., Tan, Nicholas Y. Q., Tang, Hua, Taylor, Kent D., Teo, Yik Ying, Tham, Yih Chung, Turner, Stephen T., Uitterlinden, André G., Vollenweider, Peter, Waldenberger, Melanie, Wang, Lihua, Wang, Ya Xing, Wei, Wen Bin, Williams, Christine, Yao, Jie, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B., Becker, Diane M., Boehnke, Michael, Bowden, Donald W., Chambers, John C., Deary, Ian J., Esko, Tõnu, Farrall, Martin, Franks, Paul W., Freedman, Barry I., Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Jonas, Jost Bruno, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S., Kutalik, Zoltán, Laakso, Markku, Laurie, Cathy C., Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K. E., Oldehinkel, Albertine J., Penninx, Brenda W. J. H., Polasek, Ozren, Porteous, David J., Rauramaa, Rainer, Samani, Nilesh J., Scott, Jame, Shu, Xiao-Ou, Van Der Harst, Pim, Wagenknecht, Lynne E., Wareham, Nicholas J., Watkins, Hugh, Weir, David R., Wickremasinghe, Ananda R., Wu, Tangchun, Zheng, Wei, Bouchard, Claude, Christensen, Kaare, Evans, Michele K., Gudnason, Vilmundur, Horta, Bernardo L., Kardia, Sharon L. R., Liu, Yongmei, Pereira, Alexandre C., Psaty, Bruce M., Ridker, Paul M., Van Dam, Rob M., Gauderman, W. Jame, Zhu, Xiaofeng, Mook-Kanamori, Dennis O., Fornage, Myriam, Rotimi, Charles N., Cupples, L. Adrienne, Kelly, Tanika N., Fox, Ervin R., Hayward, Caroline, Van Duijn, Cornelia M., Tai, E. Shyong, Wong, Tien Yin, Kooperberg, Charle, Palmas, Walter, Rice, Kenneth, Morrison, Alanna C., Elliott, Paul, Caulfield, Mark J., Munroe, Patricia B., Rao, Dabeeru C., Province, Michael A., Levy, Daniel, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Surgery, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, and Ehret, Georg Benedikt
Subjects: Genetics and Molecular Biology (all), Male, Erfðagreining, Áfengissýki, LOCI, Social Sciences, Blood Pressure, Genome-wide association study, Biochemistry, Vascular Medicine, TRANSCRIPTION FACTOR GATA4, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), DEPENDENCE, HEPATOCELLULAR-CARCINOMA, 80 and over, Psychology, Public and Occupational Health, Alcohol consumption, Cardiac and Cardiovascular Systems, Gene–environment interaction, ddc:616, Aged, 80 and over, [STAT.AP]Statistics [stat]/Applications [stat.AP], MESH: Middle Aged, Kardiologi, MESH: Polymorphism, Single Nucleotide, Áfengisneysla, MESH: Gene-Environment Interaction, COMMON VARIANTS, Genomics, MESH: Blood Pressure, Pedigree, 3. Good health, Näringslära, MESH: Young Adult, Physical Sciences, Medicine, Medical genetics, Erfðarannsóknir, Statistics (Mathematics), medicine.medical_specialty, Blood Pressure/genetics, Alcohol Drinking, MESH: Pedigree, Science, Genetic loci, ta3111, Genome Complexity, 03 medical and health sciences, Gene mapping, Genetics, Humans, Polymorphism, Statistical Methods, GENOME-WIDE ASSOCIATION, Molecular Biology Techniques, Molecular Biology, Alleles, Aged, MESH: Adolescent, MESH: Humans, Adolescent, Adult, Alcohol Drinking/epidemiology, Alcohol Drinking/genetics, Cohort Studies, Continental Population Groups/genetics, Continental Population Groups/statistics & numerical data, Female, Gene-Environment Interaction, Genetic Predisposition to Disease/epidemiology, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study, Hypertension/epidemiology, Hypertension/genetics, Middle Aged, Polymorphism, Single Nucleotide, Young Adult, Gene Mapping, Racial Groups, ta1182, Biology and Life Sciences, Computational Biology, MESH: Adult, Meta-analysis, 030104 developmental biology, Genetic Loci, MESH: Genome-Wide Association Study, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Female, Mathematics, MESH: Alcohol Drinking, Meta-Analysis, 0301 basic medicine, MESH: Continental Population Groups, MESH: Hypertension, Mathematical and Statistical Techniques, MESH: Aged, 80 and over, Polymorphism (computer science), Medicine and Health Sciences, FUNCTIONAL VARIATION, MESH: Cohort Studies, MESH: Aged, Alcohol Consumption, Multidisciplinary, Nutrition and Dietetics, MESH: Genetic Predisposition to Disease, Genetic Predisposition to Disease/epidemiology/genetics, Single Nucleotide, Blóðþrýstingur, ENVIRONMENT INTERACTION, PTP4A1-PHF3-EYS VARIANTS, Alcoholism, ANCESTRAIS, Háþrýstingur, Hypertension, Blood pressure, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Medical Genetics, Research Article, Substance-Related Disorders, Addiction, RISK, METAANALYSIS, Research and Analysis Methods, Mental Health and Psychiatry, medicine, Medicine [Science], Genetic Predisposition to Disease, Allele, Hypertension/epidemiology/genetics, Nutrition, Medicinsk genetik, Continental Population Groups/genetics/statistics & numerical data, business.industry, Alcohol Drinking/epidemiology/genetics, Genetic architecture, MESH: Male, Introns, Diet, BODY-MASS INDEX, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2018
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11. GWAR:robust analysis and meta-analysis of genome-wide association studies

Author: Dimou, Niki L, Tsirigos, Konstantinos D, Elofsson, Arne, Bagos, Pantelis G, Dimou, Niki L, Tsirigos, Konstantinos D, Elofsson, Arne, and Bagos, Pantelis G
Abstract: Motivation: In the context of genome-wide association studies (GWAS), there is a variety of statistical techniques in order to conduct the analysis, but, in most cases, the underlying genetic model is usually unknown. Under these circumstances, the classical Cochran-Armitage trend test (CATT) is suboptimal. Robust procedures that maximize the power and preserve the nominal type I error rate are preferable. Moreover, performing a meta-analysis using robust procedures is of great interest and has never been addressed in the past. The primary goal of this work is to implement several robust methods for analysis and meta-analysis in the statistical package Stata and subsequently to make the software available to the scientific community.Results: The CATT under a recessive, additive and dominant model of inheritance as well as robust methods based on the Maximum Efficiency Robust Test statistic, the MAX statistic and the MIN2 were implemented in Stata. Concerning MAX and MIN2, we calculated their asymptotic null distributions relying on numerical integration resulting in a great gain in computational time without losing accuracy. All the aforementioned approaches were employed in a fixed or a random effects meta-analysis setting using summary data with weights equal to the reciprocal of the combined cases and controls. Overall, this is the first complete effort to implement procedures for analysis and meta-analysis in GWAS using Stata.Availability and Implementation: A Stata program and a web-server are freely available for academic users at http://www.compgen.org/tools/GWAR.Contact: pbagos@compgen.org.Supplementary information: Supplementary data are available at Bioinformatics online.
Published: 2017

12. Next Steps for Gene Identification in Primary Hypertension Genomics

Author: Georg Ehret
Subjects: 0301 basic medicine, Genetics, ddc:616, Genomics, Biology, Heritability, Dna variants, Essential hypertension, medicine.disease, Phenotype, 03 medical and health sciences, 030104 developmental biology, Internal Medicine, medicine, Humans, Identification (biology), Essential Hypertension, Gene, Hypertension/genetics, Genetic association
Abstract: See related article, pp 743–750 Blood pressure (BP) genomics informs on the root origins of primary hypertension, which are still unclear. Since 2008, the field of BP genetics has changed with evidence accumulating from genome-wide association studies. In this issue of Hypertension , Zeller et al1 describe a different approach to BP gene discovery by using RNA expression profiles instead of DNA variants. Using DNA variants, 24 large genome-wide association studies have been published to date, and the number of new loci is steadily increasing with a large contribution from the latest studies with 150 000–320 000 individuals in the discovery phase (Table; Figure). In total, ≈300 variants have now been replicated to be associated with systolic BP and diastolic BP and their phenotypic derivatives (full list and references to individual studies at www.bloodpressuregenetics.org). Some consider the glass half-full and others half-empty on the new knowledge gained by BP genome-wide association studies. It is clear that novel findings have been added, but at the same time, much of the heritability is not yet captured by the variants identified. To date, only ≈3% to 4% of phenotypic variance is explained by the variants identified,2 translating to …
Published: 2017

13. Rare coding variants associated with blood pressure variation in 15 914 individuals of African ancestry

Author: Aravinda Chakravarti, C. Charles Gu, Alanna C. Morrison, Melissa A. Richard, Adesola Ogunniyi, Fasil Tekola-Ayele, Sharon L.R. Kardia, Bamidele O. Tayo, Erin B. Ware, Richard S. Cooper, Yun J. Sung, Babatunde L. Salako, Georg Ehret, Priyanka Nandakumar, Megan L. Grove, Dongwon Lee, Charles N. Rotimi, and Myriam Fornage
Subjects: 0301 basic medicine, Candidate gene, Blood Pressure/genetics, Genotype, Physiology, Population, Black People, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetic variation, Internal Medicine, Cardiovascular Diseases/genetics, Medicine, Humans, Exome, Risk factor, education, Genotyping, Genetics, ddc:616, education.field_of_study, business.industry, African Continental Ancestry Group/genetics, Genetic Variation, 030104 developmental biology, Genetic epidemiology, Cardiovascular Diseases, Hypertension, Cardiology and Cardiovascular Medicine, business, Hypertension/genetics, Cohort study
Abstract: Hypertension is a major risk factor for all cardiovascular diseases, especially among African Americans. This study focuses on identifying specific blood pressure (BP) genes using 15 914 individuals of African ancestry from eight cohorts (Africa America Diabetes Mellitus, Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in young Adults, Genetics Network, Genetic Epidemiology Network of Arteriopathy, Howard University Family Study, Hypertension Genetic Epidemiology Network, and Loyola University Chicago Cohort) to further genetic findings in this population which has generally been underrepresented in BP studies. We genotyped and performed various single variant and gene-based exome-wide analyses on 15 914 individuals on the Illumina HumanExome Beadchip v1.0 or v1.1 to test association with SBP and DBP long-term average residuals that were adjusted for age, age-squared, sex, and BMI. We identified rare variants affecting SBP and DBP in 10 genes: AFF1, GAPDHS, SLC28A3, COL6A1, CRYBA2, KRBA1, SEL1L3, YOD1, CCDC13, and QSOX1. Prior experimental evidence for six of these 10 candidate genes supports their involvement in cardiovascular mechanisms, corroborating their potential roles in BP regulation. Although our results require replication or validation due to their low numbers of carriers, and an ethnicity-specific genotyping array may be more informative, this study, which has identified several candidate genes in this population most susceptible to hypertension, presents one of the largest African-ancestry BP studies to date and the largest including analysis of rare variants.
Published: 2017

14. Probing genetic overlap in the regulation of systolic and diastolic blood pressure in Danish and Chinese twins

Author: Kirsten Ohm Kyvik, Zengchang Pang, Haiping Duan, Qihua Tan, Torben A Kruse, Shuxia Li, Jacob v. B. Hjelmborg, and Dongfeng Zhang
Subjects: Male, Asian Continental Ancestry Group, Adult, China, medicine.medical_specialty, Blood Pressure/genetics, Systole, Physiology, Denmark, European Continental Ancestry Group, Twins, Blood Pressure, White People, Danish, Young Adult, Asian People, Diastole, Internal medicine, Internal Medicine, Humans, Medicine, cardiovascular diseases, Registries, Chinese, business.industry, blood pressure, Middle Aged, Diastole/genetics, language.human_language, Blood pressure, Hypertension, Cardiology, language, Female, genetic overlap, Cardiology and Cardiovascular Medicine, business, Hypertension/genetics, Systole/genetics, circulatory and respiratory physiology
Abstract: Although the phenotypic correlation between systolic blood pressure (SBP) and diastolic blood pressure (DBP) is well known, the genetic basis for the correlation has rarely been investigated. The aim of this paper is to examine the genetic overlap between SBP and DBP by fitting bivariate models to Danish and Chinese twins and comparing ethnic differences between the two samples. Our estimates revealed a high proportion of additive genetic components shared by both SBP and DBP in Danish (0.71, 95% confidence interval (CI): 0.65-0.75) and Chinese (0.62, 95% CI: 0.50-0.71) twins with no statistically significant ethnic differences. The estimated genetic component in phenotypic correlation could serve to guide molecular genetic studies searching for genetic variants that affect both SBP and DBP. The bivariate model also estimated genetic and environmental contributions to SBP and DBP separately, with an overall pattern of higher genetic regulation or heritability in Danish (0.72, 95% CI: 0.67-0.76 for SBP; 0.70, 95% CI: 0.65-0.75 for DBP) than in Chinese (0.54, 95% CI: 0.44-0.63 for SBP; 0.57, 95% CI: 0.47-0.65 for DBP) twins and a higher contribution from unique environmental factors in Chinese compared with Danish twins. The estimated contribution from unique environmental factors suggests that promoting healthy lifestyles may provide an efficient way of controlling high blood pressure, particularly in the Chinese population. Although the phenotypic correlation between systolic blood pressure (SBP) and diastolic blood pressure (DBP) is well known, the genetic basis for the correlation has rarely been investigated. The aim of this paper is to examine the genetic overlap between SBP and DBP by fitting bivariate models to Danish and Chinese twins and comparing ethnic differences between the two samples. Our estimates revealed a high proportion of additive genetic components shared by both SBP and DBP in Danish (0.71, 95% confidence interval (CI): 0.65-0.75) and Chinese (0.62, 95% CI: 0.50-0.71) twins with no statistically significant ethnic differences. The estimated genetic component in phenotypic correlation could serve to guide molecular genetic studies searching for genetic variants that affect both SBP and DBP. The bivariate model also estimated genetic and environmental contributions to SBP and DBP separately, with an overall pattern of higher genetic regulation or heritability in Danish (0.72, 95% CI: 0.67-0.76 for SBP; 0.70, 95% CI: 0.65-0.75 for DBP) than in Chinese (0.54, 95% CI: 0.44-0.63 for SBP; 0.57, 95% CI: 0.47-0.65 for DBP) twins and a higher contribution from unique environmental factors in Chinese compared with Danish twins. The estimated contribution from unique environmental factors suggests that promoting healthy lifestyles may provide an efficient way of controlling high blood pressure, particularly in the Chinese population.Hypertension Research advance online publication, 15 May 2014; doi:10.1038/hr.2014.95.
Published: 2014
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15. Deletion of cyclooxygenase-2 in the mouse increases arterial blood pressure with no impairment in renal NO production in response to chronic high salt intake

Author: Rolf M. Nüsing, Kirsten Madsen, Boye L. Jensen, Mette Staehr, Pernille B. Lærkegaard Hansen, and Paul M. Vanhoutte
Subjects: Male, medicine.medical_specialty, Nitric Oxide Synthase Type III, Physiology, Prostacyclin, Stimulation, Kidney/drug effects, Kidney, Nitric Oxide, High salt intake, Cyclooxygenase 2/genetics, Mice, NaCl, Enos, Physiology (medical), Internal medicine, Sodium Chloride, Dietary/administration & dosage, Cyclic AMP, medicine, Cyclic AMP/genetics, Animals, Arterial Pressure, Sodium Chloride, Dietary, No production, Cyclic GMP, Mice, Knockout, Arterial Pressure/drug effects, biology, ENOS, Chemistry, Nitric Oxide/biosynthesis, biology.organism_classification, Mice, Inbred C57BL, Blood pressure, Endocrinology, medicine.anatomical_structure, Cyclooxygenase 2, Hypertension, Nitric Oxide Synthase Type III/genetics, biology.protein, Cyclic GMP/genetics, Female, PGE2, Cyclooxygenase, Hypertension/genetics, medicine.drug
Abstract: Experiments were designed to test the hypothesis that cyclooxygenase-2 (COX-2) activity attenuates the blood pressure increase during high NaCl intake by stimulation of endothelial nitric oxide synthase (eNOS)-mediated NO synthesis in the kidney medulla. COX-2−/−(C57BL6) an COX-2+/+mice were fed a diet with 0.004% (low salt, LS) or 4% (high salt, HS) NaCl for 18 days. Arterial blood pressure was recorded continuously using indwelling catheters. Food and water intake and diuresis were measured in metabolic cages. Urine osmolality and excretion of electrolytes, cGMP, cAMP, and NOx were determined, as well as plasma NOx and cGMP. There was a significant dependence of blood pressure on salt intake and genotype: COX-2−/−exhibited higher blood pressure than COX-2+/+both on HS and LS intake. COX-2+/+littermates displayed an increase in blood pressure on HS versus LS (102.3 ± 1.1 mmHg vs. 91.9 ± 0.9 mmHg) day and night. The mice exhibited significant blood pressure increases during the awake phase (night) that were larger in COX-2−/−on HS diet compared with COX-2+/+. Water intake, diuresis, Na+, and osmolyte excretions and NOx and cGMP excretions were significantly and similarly elevated with HS in COX-2−/−and COX-2+/+. In summary, C57BL6 mice exhibit a salt intake-dependent increase in arterial blood pressure with increased renal NO production. COX-2 activity has a general lowering effect on arterial blood pressure. COX-2 dampens NaCl-induced increases in arterial blood pressure in the awake phase. In conclusion, COX-2 activity attenuates the changes in nocturnal blood pressure during high salt intake, and COX-2 activity is not necessary for increased renal nitric oxide formation during elevated NaCl intake.
Published: 2013
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16. Quantifying the extent to which index event biases influence large genetic association studies

Author: Louise A. Donnelly, Zoltán Kutalik, Ewan R. Pearson, Marcus A. Tuke, Timothy M. Frayling, Aaron McDaid, Samuel E. Jones, Patricia B. Munroe, Andrew R. Wood, Lynne J. Hocking, Archie Campbell, Michael P. Bancks, Jessica Tyrrell, Anna Murray, Michael N. Weedon, Robin N Beaumont, Rachel M. Freathy, Caroline Hayward, Katherine S. Ruth, James S. Pankow, Hanieh Yaghootkar, and Colin N. A. Palmer
Subjects: Blood Glucose, 0301 basic medicine, Index (economics), Diabetes risk, Genotype, Population, Library science, Disease, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Body Mass Index, 03 medical and health sciences, Alleles, Blood Glucose/genetics, Diabetes Mellitus, Type 2/genetics, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Hypertension/genetics, Hypertension/pathology, Obesity/genetics, Genetics, Medicine, Obesity, Allele, Aric study, education, Molecular Biology, Genetics (clinical), Genetic association, Government, education.field_of_study, business.industry, European research, Association Studies Articles, General Medicine, Medical research, medicine.disease, Biobank, NASA Chief Scientist, Atherosclerosis Risk in Communities, 030104 developmental biology, Diabetes Mellitus, Type 2, Hypertension, Trait, business, TCF7L2, Demography
Abstract: The Wellcome Trust provides support for Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) and informatics support is provided by the Chief Scientist Office. The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. H.Y., A.R.W. and T.M.F. are supported by the European Research Council grant: 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. Z.K. received financial support from the Leenaards Foundation, the Swiss Institute of Bioinformatics and the Swiss National Science Foundation (31003A-143914) and SystemsX.ch ((40)). The work of M.P.B was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number T32HL007779. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. E.R.P. holds a WT New investigator award 102820/Z/13/Z.
Published: 2016
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17. High Blood Pressure in Adolescents of Curitiba: Prevalence and Associated Factors

Author: Bozza, Rodrigo, Campos, Wagner de, Barbosa Filho, Valter Cordeiro, Stabelini Neto, Antonio, Silva, Michael Pereira da, and Maziero, Renato Silva Barbosa
Subjects: Fatores de Risco, Adolescent, Circunferência da Cintura, Risk Factors, Hipertensão / genética, Arterial Blood Pressure, Pressão Arterial, Waist Circumference, Hypertension/genetics, Adolescente
Abstract: Background: Arterial hypertension is a major public health problem and has increased considerably in young individuals in past years. Thus, identifying factors associated with this condition is important to guide intervention strategies in this population. Objective: To determine high blood pressure prevalence and its associated factors in adolescents. Methods: A random sample of 1,242 students enrolled in public schools of the city of Curitiba (PR) was selected. Self-administered questionnaires provided family history of hypertension, daily energy expenditure, smoking habit, daily fat intake, and socioeconomic status. Waist circumference was measured following standardized procedures, and blood pressure was measured with appropriate cuffs in 2 consecutive days to confirm high blood pressure. Relative frequency and confidence interval (95%CI) indicated high blood pressure prevalence. Bivariate and multivariate analyses assessed the association of risk factors with high blood pressure. Results: The high blood pressure prevalence was 18.2% (95%CI 15.2-21.6). Individuals whose both parents had hypertension [odds ratio (OR), 2.22; 95%CI 1.28-3.85] and those with high waist circumference (OR, 2.1; 95%CI 1.34-3.28) had higher chances to develop high blood pressure. Conclusion: Positive family history of hypertension and high waist circumference were associated with high blood pressure in adolescents. These factors are important to guide future interventions in this population. Resumo Fundamento: A hipertensão arterial é um grave problema de saúde pública e, nos últimos anos, tem aumentado consideravelmente em jovens. A identificação de fatores associados com essa condição é importante para guiar estratégias de intervenção nessa população. Objetivo: Determinar a prevalência e os fatores associados com a pressão arterial alterada em adolescentes. Métodos: Foi selecionada amostra probabilística de 1.242 adolescentes da rede pública de ensino de Curitiba (PR). Por meio de questionários, foram obtidos o histórico familiar de hipertensão, o gasto energético diário, informações sobre tabagismo, o consumo diário de gorduras e a classificação econômica. A circunferência da cintura foi medida por procedimentos padronizados. A pressão arterial foi aferida com manguitos adequados em 2 dias consecutivos para a confirmação da pressão arterial alterada. Frequências relativas e intervalos de confiança (IC95%) indicaram a prevalência de pressão arterial alterada. Regressões logística bivariadas e multivariadas testaram a associação dos fatores de risco com a pressão arterial alterada. Resultados: A prevalência de pressão arterial alterada foi de 18,2% (IC95% 15,2-21,6). Mais chances de pressão arterial alterada foram encontradas nos indivíduos que possuíam ambos os pais com hipertensão arterial [odds ratio (OR), 2,22; IC95% 1,28-3,85] e naqueles com a circunferência da cintura aumentada (OR, 2,1; IC95% 1,34-3,28). Conclusão: O histórico familiar positivo de hipertensão arterial e a circunferência da cintura aumentada estiveram associados a pressão arterial alterada em adolescentes. Esses fatores são importantes para guiar intervenções futuras nessa população.
Published: 2016

18. High Blood Pressure in Adolescents of Curitiba: Prevalence and Associated Factors

Author: Renato Silva Barbosa Maziero, Wagner de Campos, Michael Pereira da Silva, Rodrigo Bozza, Valter Cordeiro Barbosa Filho, and Antonio Stabelini Neto
Subjects: Male, Fatores de Risco, medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, Waist, Multivariate analysis, Adolescent, Circunferência da Cintura, Population, Blood Pressure, 030204 cardiovascular system & hematology, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Risk Factors, Humans, Medicine, Arterial Blood Pressure, Sex Distribution, Family history, education, Socioeconomic status, Adolescente, education.field_of_study, 030505 public health, business.industry, Original Articles, Odds ratio, Confidence interval, Blood pressure, lcsh:RC666-701, Hipertensão / genética, Hypertension, Physical therapy, Female, Pressão Arterial, Waist Circumference, Epidemiologic Methods, 0305 other medical science, Cardiology and Cardiovascular Medicine, business, Hypertension/genetics, Brazil, Systemic Hypertension, Demography
Abstract: Background: Arterial hypertension is a major public health problem and has increased considerably in young individuals in past years. Thus, identifying factors associated with this condition is important to guide intervention strategies in this population. Objective: To determine high blood pressure prevalence and its associated factors in adolescents. Methods: A random sample of 1,242 students enrolled in public schools of the city of Curitiba (PR) was selected. Self-administered questionnaires provided family history of hypertension, daily energy expenditure, smoking habit, daily fat intake, and socioeconomic status. Waist circumference was measured following standardized procedures, and blood pressure was measured with appropriate cuffs in 2 consecutive days to confirm high blood pressure. Relative frequency and confidence interval (95%CI) indicated high blood pressure prevalence. Bivariate and multivariate analyses assessed the association of risk factors with high blood pressure. Results: The high blood pressure prevalence was 18.2% (95%CI 15.2-21.6). Individuals whose both parents had hypertension [odds ratio (OR), 2.22; 95%CI 1.28-3.85] and those with high waist circumference (OR, 2.1; 95%CI 1.34-3.28) had higher chances to develop high blood pressure. Conclusion: Positive family history of hypertension and high waist circumference were associated with high blood pressure in adolescents. These factors are important to guide future interventions in this population.
Published: 2016

19. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author: Timo A. Lakka, Kathleen Stirrups, Jean Ferrières, Ying Wu, Gulum Kosova, Toby Johnson, Heather M. Stringham, Bruce M. Psaty, Bruna Gigante, Göran Hallmans, Cornelia M. van Duijn, Kae Woei Liang, Niclas Eriksson, N. William Rayner, Lynda M. Rose, Stavroula Kanoni, Xueling Sim, Evangelos Evangelou, Philippe Froguel, Michel Burnier, Andrew P. Morris, Olle Melander, Martin Farrall, Albert V. Smith, Brendan J. Keating, Thomas Illig, Johan Sundström, Dorret I. Boomsma, Kate Witkowska, Ellen M. Schmidt, Aki S. Havulinna, Ann-Kristin Petersen, Paul F. O'Reilly, Young Jin Kim, Kari Kuulasmaa, Tom Wilsgaard, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Rona J. Strawbridge, Ronald M. Krauss, Fotios Drenos, Stuart K. Kim, Ken K. Ong, Pascal Bovet, Danish Saleheen, Jaspal S. Kooner, Karl-Heinz Herzig, Tien Yin Wong, Benjamin F. Voight, Stefania Bandinelli, Stéphane Lobbens, Colin A. McKenzie, Jing Hua Zhao, Terrence Forrester, Louise A. Donnelly, Alice Stanton, Jean Dallongeville, Kirill V. Tarasov, Narisu Narisu, Jürgen Gräßler, Luigi Ferrucci, Peter S. Sever, Paul Elliott, Tune H. Pers, Andrew J. Smith, Tomas Axelsson, Young Ah Shin, Nora Franceschini, James F. Wilson, Vilmundur Gudnason, Kati Kristiansson, Andrew A. Hicks, Kent D. Taylor, Genovefa Kolovou, Andrew D. Morris, André G. Uitterlinden, Serena Sanna, Xiuqing Guo, Honghuang Lin, Aravinda Chakravarti, Wayne Huey-Herng Sheu, Panos Deloukas, Linda S. Adair, Diana Kuh, Murielle Bochud, Eric Boerwinkle, Inger Njølstad, Meena Kumari, Norman Klopp, Leo-Pekka Lyytikäinen, Steven C. Hunt, Weihua Zhang, Tõnu Esko, Pierre Meneton, Markus Perola, Erik P A Van Iperen, Georg Ehret, Veikko Salomaa, Lars Lind, Zoltán Kutalik, Cristiano Fava, Caroline Hayward, Hugh S. Markus, Teresa Ferreira, Stefan R. Bornstein, Vasyl Pihur, Patricia B. Munroe, Anne U. Jackson, Eirini Marouli, Gabriele Müller, Damiano Baldassarre, Jacques E. Rossouw, Dan E. Arking, Maija Hassinen, Nicholas J. Wareham, Robert Roberts, Daniel I. Chasman, I. Shou Chang, Sylvain Sebert, Tove Fall, Roby Joehanes, Patrik K. E. Magnusson, John C. Chambers, Peter Vollenweider, Wen Jane Lee, Dmitry Shungin, Mathias Gorski, Christopher Newton-Cheh, Anders Franco-Cereceda, Ching-Yu Cheng, Yun Kyoung Kim, Ruth J. F. Loos, Lude Franke, Karen L. Mohlke, Yii-Der Ida Chen, Carlos Iribarren, Martina Müller-Nurasyid, Alexander Teumer, Andrew D. Johnson, Antonella Mulas, Ulf Gyllensten, Martin D. Tobin, George Dedoussis, Rainford J. Wilks, Joshua C. Bis, Beverley Balkau, Jie Yao, Frida Renström, Themistocles L. Assimes, Morris Brown, Inês Barroso, Hyun Min Kang, Loic Yengo, Mika Kähönen, Christopher J. Groves, Kirsti Kvaløy, Rainer Rauramaa, Heribert Schunkert, Satu Männistö, Marjo-Riitta Järvelin, Nancy L. Pedersen, Karl Gertow, Rick Jansen, Thomas Quertermous, Jarmo Virtamo, Lazaros Lataniotis, Serge Hercberg, Paul M. Ridker, Osorio Meirelles, Jostein Holmen, Phil Howard, G. Kees Hovingh, Jeanette Erdmann, Jong-Young Lee, Peter Schwarz, Ramaiah Nagaraja, Elizabeth Theusch, Wei Zhao, Sonia Shah, Chao A. Hsiung, Santhi K. Ganesh, Richard S. Cooper, John M. C. Connell, Jian'an Luan, Graciela E. Delgado, Eric Kim, Daniel Levy, Li Lin, Jerome I. Rotter, Andres Metspalu, Nabila Bouatia-Naji, Christopher J. O'Donnell, Roberto Elosua, Andrew Wong, Alanna C. Morrison, Juha Saltevo, Michael R. Barnes, Alan B. Weder, Kay-Tee Khaw, Leena Moilanen, Peter S. Chines, Claudia Langenberg, Marika Kaakinen, Asif Rasheed, Annette Peters, Angela Döring, Alena Stančáková, Richard A. Jensen, Jaana Lindström, Alison H. Goodall, Toshiko Tanaka, Loukianos S. Rallidis, Dabeeru C. Rao, Ann-Christine Syvänen, Alun Evans, Brenda W.J.H. Penninx, Sarah Edkins, Xiaohui Li, Neil Poulter, Jouko Saramies, Ulf de Faire, Walter Palmas, Jaakko Tuomilehto, Louise V. Wain, Cristina Menni, Stephen Bevan, Maria X. Sosa, Nanette R. Lee, Anuj Goel, Germaine C. Verwoert, Kjell Nikus, Helen R. Warren, May E. Montasser, Ren-Hua Chung, Francesco Gianfagna, Kristian Hveem, Rainer Rettig, Unnur Thorsteinsdottir, Lori L. Bonnycastle, Tim D. Spector, Paul W. Franks, Bamidele O. Tayo, Ilja M. Nolte, John Danesh, E. Shyong Tai, Mika Kivimäki, Devin Absher, Oddgeir L. Holmen, Per Eriksson, Pirjo Komulainen, Peter P. Pramstaller, Cameron D. Palmer, He Gao, Elena Tremoli, H.-Erich Wichmann, Myriam Fornage, Gyda Bjornsdottir, Afshin Parsa, Anders Hamsten, Terho Lehtimäki, Lasse Folkersen, Janine F. Felix, Anna F. Dominiczak, Hinco J. Gierman, Edward G. Lakatta, Alex S. F. Doney, Erik Ingelsson, Colin N. A. Palmer, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Vladan Mijatovic, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Stefan Enroth, Mark J. Caulfield, Gudmar Thorleifsson, Tsun-Po Yang, François Mach, Cristen J. Willer, Claudia P. Cabrera, Aline Wagner, Michael Boehnke, Elias Salfati, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Harm-Jan Westra, Harold Snieder, Mark O. Goodarzi, M. Arfan Ikram, Fred Paccaud, Johannes H. Smit, Anna-Liisa Hartikainen, Xiaofeng Zhu, Markku Laakso, Ahmad Vaez, Albert Hofman, Amy J. Swift, Maria Hughes, I. Te Lee, Aroon D. Hingorani, Matti Uusitupa, Oscar H. Franco, Kenneth Rice, Veronique Vitart, Ross M. Fraser, Jouke-Jan Hottenga, Kari Stefansson, Dhananjay Vaidya, Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Saw Swee Hock School of Public Health, National University of Singapore (NUS), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan System, Department of Computational Medicine and Bioinformatics (DCM&B), Queen Mary University of London (QMUL), GlaxoSmithKline, Glaxo Smith Kline, deCODE genetics [Reykjavik], University of Cambridge [UK] (CAM), University of Dundee, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Karolinska University Hospital [Stockholm], Umea University Hospital, Lund University [Lund], Queen's University [Belfast] (QUB), National Institutes of Health, Department of Genomics of Common Disease, Imperial College London, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), National Institute of Health and Welfare, Institute for Molecular Medicine Finland (FIMM), University College London Hospitals (UCLH), University Hospital of Heidelberg, Harbor UCLA Medical Center [Torrance, Ca.], University of Tampere, University of Verona (UNIVR), Uppsala University Hospital, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Stanford University School of Medicine [CA, USA], Medical School University of Athens, Partenaires INRAE, Children's Hospital Oakland Research Institute, Boston Children's Hospital, Broad Institute of Harvard and MIT, University of Copenhagen = Københavns Universitet (KU), Statens Serum Institut [Copenhagen], Framingham Heart Dis Epidemiol Study, Department of Psychiatry, VU University Medical Center [Amsterdam], National Heart, Lung and Blood Institute, Osong Health Technology Administration Complex, University of Pennsylvania, Department of Genetics, University of North Carolina at Chapel Hill (UNC), Loyola University [Chicago], Centre Hospitalier Universitaire Vaudois (CHUV), Hudson Alpha Institute for Biotechnology, Erasmus University Rotterdam, Department of Medical Sciences, Uppsala University, Università degli Studi di Milano [Milano] (UNIMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], University of Lincoln, University of Washington [Seattle], Amgen Inc., The University of Texas Health Science Center at Houston (UTHealth), VU University Amsterdam, University of Dresden Medical School, Université de Lausanne (UNIL), Healthcare NHS Trust, National Health Research Institutes, National University Health System [Singapore] (NUHS), Duke-NUS Medical School [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National Human Genome Research Institute (NHGRI), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Radiology and nuclear medicine, EMGO - Mental health, Lin, Li, Mach, François, ProdInra, Migration, University of Oxford, Università degli studi di Verona = University of Verona (UNIVR), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO+ - Lifestyle, Overweight and Diabetes, Biological Psychology, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Danesh, John [0000-0003-1158-6791], Khaw, Kay-Tee [0000-0002-8802-2903], Markus, Hugh [0000-0002-9794-5996], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Medical Microbiology & Infectious Diseases, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, Biochemistry, National Institute for Health Research, and Medical Research Council (MRC)
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), CHROMATIN, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Blood Pressure, SUSCEPTIBILITY, Bioinformatics, Cardiovascular, Genome-wide association studies, Medical and Health Sciences, single nucleotide polymorphism, CHARGE-EchoGen consortium, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, African Continental Ancestry Group, Genetics & Heredity, Genetics, ddc:616, Kidney, Framingham Risk Score, Cultured, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, African Continental Ancestry Group/genetics, Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Hypertension/pathology, Microarray Analysis, Polymorphism, Single Nucleotide, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypertension/genetics/pathology, Hypertension, Medical genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, TRAITS, Biotechnology, Asian Continental Ancestry Group, medicine.medical_specialty, CHARGE-EchoGen Consortium, Cells, Black People, BIOLOGY, Single-nucleotide polymorphism, Biology, Blood pressure, hypertension, genetics, single nucleotide polymorphism, GWAS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, CELL-TYPES, METAANALYSIS, Genetic association, Science & Technology, CHARGE-HF consortium, 06 Biological Sciences, Genetic architecture, 030104 developmental biology, Blood pressure, CHARGE-HF Consortium, ARTERIAL-HYPERTENSION, Developmental Biology
Abstract: To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.
Published: 2016
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20. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Author: M. Tang, S. Y. Kim, Tom Forsén, Yun Li, Q. Li, Karina Banasik, J. M. Dekker, Leif Groop, B. Balkau, N. van Leeuwen, Jacek Mokrosinski, G. Tian, Alex S. F. Doney, Thue W. Schwartz, H. Jiang, Johanna Kuusisto, Thorfinn Sand Korneliussen, S. Huang, Guillaume Charpentier, Giel Nijpels, Daniel R. Witte, Maria Lajer, Alena Stančáková, F. Xi, Oluf Pedersen, Anders Albrechtsen, Torben Jørgensen, Mozhgan Dorkhan, Torben Hansen, Amanda J. Bennett, B. Wang, Gregers S. Andersen, Chang Yu, Aneta Aleksandra Nielsen, Mark I. McCarthy, Lise Tarnow, Markku Laakso, Timothy M. Frayling, P.E. Slagboom, Olov Rolandsson, Y. Wang, Torsten Lauritzen, Christopher J. Groves, Weihua Zhang, Peter M. Nilsson, T. Jiang, Loic Yengo, Leen M 't Hart, Y. Gui, Tiinamaija Tuomi, Chao Nie, Peter Rossing, J. Zhang, Frida Renström, Andrew D. Morris, Cramer Christensen, Graham A. Hitman, Neil Robertson, H. Cao, Göran Hallmans, Allan Linneberg, Niels Grarup, Line Skotte, H. Wu, Colin N. A. Palmer, M. P. Manijak, Q. Zhang, Andrew P. Morris, Rasmus Ribel-Madsen, Yi Chen, Arne Astrup, Tibor V. Varga, Mark Walker, Y. Zhou, Jun Wang, Maria Sterner, Paul W. Franks, Lars Bolund, Andrew T. Hattersley, Johan Holmkvist, Karsten Kristiansen, David Altshuler, E. van 't Riet, Philippe Froguel, Stéphane Cauchi, R. Wu, Kunlun He, B. Mu, X. Ma, X. Liu, Weijing Li, H. Liang, Rasmus Nielsen, Olivier Lantieri, T. Ma, Xin Jin, Claes Ladenvall, Michel Marre, Nigel W. Rayner, Thomas Sparsø, Marie A. Vestmar, Johanne Marie Justesen, Ivan Brandslund, Q. Liao, Xiaoming Zhang, H. Zheng, Epidemiology and Data Science, General practice, EMGO - Lifestyle, overweight and diabetes, Massachusetts Institute of Technology. Department of Biology, and Altshuler, David
Subjects: Exome/genetics, Exome sequencing, Endocrinology, Diabetes and Metabolism, IDENTIFIES 6, EFFICIENT, Genome-wide association study, VARIANTS, 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Genetic epidemiology, Exome, Polymorphism, Genetic/genetics, RISK, Genetics, 0303 health sciences, High-Throughput Nucleotide Sequencing, Type 2 diabetes, Polymorphism, Single Nucleotide/genetics, Lipids, Gene Frequency/genetics, Hypertension, Diabetes Mellitus, Type 2/genetics, Genotype, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, DNA sequencing, Article, 03 medical and health sciences, Internal Medicine, Humans, Obesity, GENOME-WIDE ASSOCIATION, Allele frequency, METAANALYSIS, 030304 developmental biology, Polymorphism, Genetic, DIABETES SUSCEPTIBILITY LOCI, Minor allele frequency, INDIVIDUALS, Diabetes Mellitus, Type 2, DE-NOVO MUTATIONS, Next-generation sequencing, GLUCOSE-HOMEOSTASIS, Hypertension/genetics
Abstract: Aims/hypothesis Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. Methods The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10). Conclusions/interpretation We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Published: 2012
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21. Lack of association between connexin40 polymorphisms and coronary artery disease

Author: Sylvie Dunoyer-Geindre, Brenda R. Kwak, François Mach, Bernard Foglia, Gerard Pasterkamp, Jacques-Antoine Haefliger, Sander W. van der Laan, Richard W. James, Anna Pfenniger, and Stephan Winnik
Subjects: Male, medicine.medical_specialty, Pathology, Endothelium, Connexin, Disease, Connexins/genetics, Coronary Artery Disease, 030204 cardiovascular system & hematology, ddc:616.07, Gastroenterology, Culprit, Connexins, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, Human Umbilical Vein Endothelial Cells, Humans, Plaque, Atherosclerotic/pathology, Promoter Regions, Genetic, 030304 developmental biology, Aged, ddc:616, 0303 health sciences, Polymorphism, Genetic, business.industry, Coronary Artery Disease/genetics, Promoter, Middle Aged, medicine.disease, Plaque, Atherosclerotic, 3. Good health, medicine.anatomical_structure, Hypertension, Female, Gene polymorphism, Cardiology and Cardiovascular Medicine, business, Hypertension/genetics
Abstract: Objective Cx40 is a gap junction protein important for cell-cell communication in the endothelium. Polymorphisms in the promoter region of the human Cx40 gene, −44G>A and +71A>G, were shown to reduce Cx40 transcription by half. As mice with an endothelial-specific deletion of Cx40 are more susceptible to atherosclerosis, this study was designed to discover a correlation between these polymorphisms and atherosclerosis in European populations. Methods and results 803 patients referred to the Geneva University Hospitals for elective coronary angiography were divided according to the number of significantly stenosed vessels (from 0 to 3) and were genotyped for the Cx40 polymorphisms. Genotype distribution in the control group was −44GG/+71AA=59.8%, −44AG/+71AG=35.1% and −44AA/+71GG=5.2%. Surprisingly, this distribution was similar in the CAD group, with −44GG/+71AA=58.5%, −44AG/+71AG=37.6% and −44AA/+71GG=3.8% ( p =0.67). Moreover, no significant association between histological carotid plaque composition of culprit lesions and Cx40 polymorphisms could be detected in 583 Dutch patients of the Athero-Express study. Conclusions Despite a clear antiatherogenic role of Cx40 in mice, our study could not detect an association of Cx40 promoter polymorphisms and CAD in human. Moreover, a correlation with atherosclerotic plaque stability or hypertension could not be demonstrated either. Connexin polymorphisms affecting channel function may be of greater importance for cardiovascular disease than polymorphisms affecting the expression level of the protein.
Published: 2012
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22. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Author: Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'an, Arora, Pankaj, Dehghan, Abbas, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, McArdle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthias, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johannes, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inês, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Markus, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margus, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, McKenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thomas, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, James, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr. , W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Anders, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcus, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Panos, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Janos, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charles, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Maris, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang H, Knowles J, Hlatky M, Fortmann S, Assimes TL, Quertermous T, Go A, Iribarren C, Absher D, Risch N, Meyers R, Sidney S, Ziegler A, Schillert A, Bickel C, Sinning C, Rupprecht HJ, Lackner K, Wild P, Schnabel R, Blankenberg S, Zeller T, Münzel T, Perret C, Cambien F, Tiret L, Nicaud V, Proust C, Dehghan A, Hofman A, Uitterlinden A, van Duijn C, Levy D, Whitteman J, Cupples LA, Demissie-Banjaw S, Ramachandran V, Smith A, Gudnason V, Boerwinkle E, Folsom A, Morrison A, Psaty BM, Chen IY, Rotter JI, Bis J, Volcik K, Rice K, Taylor KD, Marciante K, Smith N, Glazer N, Heckbert S, Harris T, Lumley T, Kong A, Thorleifsson G, Thorgeirsson G, Holm H, Gulcher JR, Stefansson K, Andersen K, Gretarsdottir S, Thorsteinsdottir U, Preuss M, Schreiber S, Meitinger T, König IR, Lieb W, Hengstenberg C, Schunkert H, Erdmann J, Fisher M, Grosshennig A, Medack A, Stark K, Linsel-Nitschke P, Bruse P, Aherrahrou Z, Peters A, Loley C, Willenborg C, Nahrstedt J, Freyer J, Gulde S, Doering A, Meisinger C, Wichmann HE, Klopp N, Illig T, Meinitzer A, Tomaschitz A, Halperin E, Dobnig H, Scharnagl H, Kleber M, Laaksonen R, Pilz S, Grammer TB, Stojakovic T, Renner W, März W, Böhm BO, Winkelmann BR, Winkler K, Hoffmann M, O'Donnell CJ, Voight BF, Altshuler D, Siscovick DS, Musunuru K, Peltonen L, Barbalic M, Melander O, Elosua R, Kathiresan S, Schwartz SM, Salomaa V, Guiducci C, Burtt N, Gabriel SB, Stewart AF, Wells GA, Chen L, Jarinova O, Roberts R, McPherson R, Dandona S, Pichard AD, Rader DJ, Devaney J, Lindsay JM, Kent KM, Qu L, Satler L, Burnett MS, Li M, Reilly MP, Wilensky R, Waksman R, Epstein S, Mattha W, Knouf CW, Waterworth DM, Hakonarson HH, Walker M, Mooser V, Hall AS, Balmforth AJ, Wright BJ, Nelson C, Thompson JR, Samani NJ, Braund PS, Ball SG, Smith NL, Felix JF, Morrison AC, Demissie S, Glazer NL, Loehr LR, Rosamond WD, Rivadeneira F, Bis JC, Folsom AR, Benjamin E, Aulchenko YS, Haritunians T, Couper D, Murabito J, Wang YA, Stricker B, Gottdiener JS, Chang PP, Wang TJ, Rice KM, Heckbert SR, Fox ER, Uitterlinden AG, Willerson JT, van Duijn CM, Witteman JC, Vasan RS, Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Parsa A, Gao X, Yang Q, Smith AV, O'Connell JR, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson A, Teumer A, Paré G, Atkinson EJ, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tönjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Struchalin M, Cavalieri M, Singleton A, Giallauria, Francesco, Metter J, de Boer J, Siscovick D, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turne ST, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Imboden M, Nitsch D, Brandstätter A, Kollerits B, Kedenko L, Mägi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Völzke H, Kroemer HK, Nauck M, Völker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, Borecki I, Krämer BK, Rudan I, Gyllensten U, Wilson JF, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS, Vasan R, Felix SB, Watzinger N, Larson MG, Homuth G, Aragam J, Dörr M, Zweiker R, Lind L, Rodeheffer RJ, Greiser KH, Deckers JW, Stritzke J, Lackner KJ, Ingelsson E, Kullo I, Haerting J, Stricker BH, Reffelmann T, Redfield MM, Werdan K, Mitchell GF, Arnett D, Blettner M, Friedrich N, Benjamin EJ, Chambers JC, Zhang W, Lord GM, van der Harst P, Lawlor DA, Sehmi JS, Gale DP, Wass MN, Ahmadi KR, Bakker SJ, Beckmann J, Bilo HJ, Bochud M, Brown MJ, Caulfield MJ, Connell JM, Cook HT, Cotlarciuc I, Davey Smith G, de Silva R, Deng G, Devuyst O, Dikkeschei LD, Dimkovic T, Dockrell M, Dominiczak A, Ebrahim S, Eggermann T, Farrall M, Floege J, Forouhi NG, Gansevoort RT, Han X, Hedblad B, Homan van der Heide JJ, Hepkema BG, Hernandez-Fuentes M, Hypponen E, Johnson T, de Jong PE, Kleefstra N, Lagou V, Lapsley M, Li Y, Loos RJ, Luan J, Luttropp K, Maréchal C, Munroe PB, Nordfors L, Penninx BW, Perucha E, Pouta A, Roderick PJ, Ruokonen A, Sanna S, Schalling M, Schlessinger D, Schlieper G, Seelen MA, Sjögren M, Smit JH, Snieder H, Soranzo N, Spector TD, Stenvinkel P, Sternberg MJ, Swaminathan R, Ubink-Veltmaat LJ, Uda M, Vollenweider P, Wallace C, Waterworth D, Zerres K, Waeber G, Wareham NJ, Maxwell PH, McCarthy MI, Jarvelin MR, Abecasis GR, Lightstone L, Scott J, Navis G, Elliot P, Kooner JS., AII - Amsterdam institute for Infection and Immunity, Nephrology, Epidemiologie, RS: CARIM School for Cardiovascular Diseases, Epidemiology, Medical Microbiology & Infectious Diseases, Radiology & Nuclear Medicine, Cardiology, Internal Medicine, Clinical Genetics, Erasmus MC other, Obstetrics & Gynecology, International Consortium for Blood Pressure Genome-Wide Association Studies, CARDIoGRAM consortium, CKDGen Consortium, KidneyGen Consortium, EchoGen consortium, CHARGE-HF consortium, Zhao, Jing Hua [0000-0003-4930-3582], Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Khaw, Kay-Tee [0000-0002-8802-2903], Danesh, John [0000-0003-1158-6791], Soranzo, Nicole [0000-0003-1095-3852], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Clinical Pharmacology and The Genome Centre, Queen Mary University of London (QMUL), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Center for Human Genetic Research, Massachusetts General Hospital [Boston], Program in Medical and Population Genetics, Harvard University-Massachusetts Institute of Technology (MIT), Ehret, Georg B., Munroe, Patricia B., Rice, Kenneth M., Bochud, Murielle, Johnson, Andrew D., Chasman, Daniel I., Smith, Albert V., Tobin, Martin D., Verwoert, Germaine C., Hwang, Shih-Jen, Pihur, Vasyl, Vollenweider, Peter, O'Reilly, Paul F., Amin, Najaf, Bragg-Gresham, Jennifer L., Teumer, Alexander, Glazer, Nicole L., Launer, Lenore, Zhao, Jing Hua, Aulchenko, Yurii, Heath, Simon, Sober, Siim, Parsa, Afshin, Luan, Jian'An, Arora, Pankaj, Dehghan, Abba, Zhang, Feng, Lucas, Gavin, Hicks, Andrew A., Jackson, Anne U., Peden, John F., Tanaka, Toshiko, Wild, Sarah H., Rudan, Igor, Igl, Wilmar, Milaneschi, Yuri, Parker, Alex N., Fava, Cristiano, Chambers, John C., Fox, Ervin R., Kumari, Meena, Go, Min Jin, van der Harst, Pim, Kao, Wen Hong Linda, Sjögren, Marketa, Vinay, D. G., Alexander, Myriam, Tabara, Yasuharu, Shaw-Hawkins, Sue, Whincup, Peter H., Liu, Yongmei, Shi, Gang, Kuusisto, Johanna, Tayo, Bamidele, Seielstad, Mark, Sim, Xueling, Hoang Nguyen, Khanh-Dung, Lehtimäki, Terho, Matullo, Giuseppe, Wu, Ying, Gaunt, Tom R., Charlotte Onland-Moret, N., Cooper, Matthew N., Platou, Carl G. P., Org, Elin, Hardy, Rebecca, Dahgam, Santosh, Palmen, Jutta, Vitart, Veronique, Braund, Peter S., Kuznetsova, Tatiana, Uiterwaal, Cuno S. P. M., Adeyemo, Adebowale, Palmas, Walter, Campbell, Harry, Ludwig, Barbara, Tomaszewski, Maciej, Tzoulaki, Ioanna, Palmer, Nicholette D., Aspelund, Thor, Garcia, Melissa, Chang, Yen-Pei C., O'Connell, Jeffrey R., Steinle, Nanette I., Grobbee, Diederick E., Arking, Dan E., Kardia, Sharon L., Morrison, Alanna C., Hernandez, Dena, Najjar, Samer, Mcardle, Wendy L., Hadley, David, Brown, Morris J., Connell, John M., Hingorani, Aroon D., Day, Ian N. M., Lawlor, Debbie A., Beilby, John P., Lawrence, Robert W., Clarke, Robert, Hopewell, Jemma C., Ongen, Halit, Dreisbach, Albert W., Li, Yali, Hunter Young, J., Bis, Joshua C., Kähönen, Mika, Viikari, Jorma, Adair, Linda S., Lee, Nanette R., Chen, Ming-Huei, Olden, Matthia, Pattaro, Cristian, Bolton, Judith A Hoffman, Köttgen, Anna, Bergmann, Sven, Mooser, Vincent, Chaturvedi, Nish, Frayling, Timothy M., Islam, Muhammad, Jafar, Tazeen H., Erdmann, Jeanette, Kulkarni, Smita R., Bornstein, Stefan R., Grässler, Jürgen, Groop, Leif, Voight, Benjamin F., Kettunen, Johanne, Howard, Philip, Taylor, Andrew, Guarrera, Simonetta, Ricceri, Fulvio, Emilsson, Valur, Plump, Andrew, Barroso, Inê, Khaw, Kay-Tee, Weder, Alan B., Hunt, Steven C., Sun, Yan V., Bergman, Richard N., Collins, Francis S., Bonnycastle, Lori L., Scott, Laura J., Stringham, Heather M., Peltonen, Leena, Perola, Marku, Vartiainen, Erkki, Brand, Stefan-Martin, Staessen, Jan A., Wang, Thomas J., Burton, Paul R., Artigas, Maria Soler, Dong, Yanbin, Snieder, Harold, Wang, Xiaoling, Zhu, Haidong, Lohman, Kurt K., Rudock, Megan E., Heckbert, Susan R., Smith, Nicholas L., Wiggins, Kerri L., Doumatey, Ayo, Shriner, Daniel, Veldre, Gudrun, Viigimaa, Margu, Kinra, Sanjay, Prabhakaran, Dorairaj, Tripathy, Vikal, Langefeld, Carl D., Rosengren, Annika, Thelle, Dag S., Corsi, Anna Maria, Singleton, Andrew, Forrester, Terrence, Hilton, Gina, Mckenzie, Colin A., Salako, Tunde, Iwai, Naoharu, Kita, Yoshikuni, Ogihara, Toshio, Ohkubo, Takayoshi, Okamura, Tomonori, Ueshima, Hirotsugu, Umemura, Satoshi, Eyheramendy, Susana, Meitinger, Thoma, Wichmann, H. -Erich, Cho, Yoon Shin, Kim, Hyung-Lae, Lee, Jong-Young, Scott, Jame, Sehmi, Joban S., Zhang, Weihua, Hedblad, Bo, Nilsson, Peter, Smith, George Davey, Wong, Andrew, Narisu, Narisu, Stančáková, Alena, Raffel, Leslie J., Yao, Jie, Kathiresan, Sekar, O'Donnell, Christopher J., Schwartz, Stephen M., Arfan Ikram, M., Longstreth Jr., W. T., Mosley, Thomas H., Seshadri, Sudha, Shrine, Nick R. G., Wain, Louise V., Morken, Mario A., Swift, Amy J., Laitinen, Jaana, Prokopenko, Inga, Zitting, Paavo, Cooper, Jackie A., Humphries, Steve E., Danesh, John, Rasheed, Asif, Goel, Anuj, Hamsten, Ander, Watkins, Hugh, Bakker, Stephan J. L., van Gilst, Wiek H., Janipalli, Charles S., Radha Mani, K., Yajnik, Chittaranjan S., Hofman, Albert, Mattace-Raso, Francesco U. S., Oostra, Ben A., Demirkan, Ayse, Isaacs, Aaron, Rivadeneira, Fernando, Lakatta, Edward G., Orru, Marco, Scuteri, Angelo, Ala-Korpela, Mika, Kangas, Antti J., Lyytikäinen, Leo-Pekka, Soininen, Pasi, Tukiainen, Taru, Würtz, Peter, Twee-HeeOng, Rick, Dörr, Marcu, Kroemer, Heyo K., Völker, Uwe, Völzke, Henry, Galan, Pilar, Hercberg, Serge, Lathrop, Mark, Zelenika, Diana, Deloukas, Pano, Mangino, Massimo, Spector, Tim D., Zhai, Guangju, Meschia, James F., Nalls, Michael A., Sharma, Pankaj, Terzic, Jano, Kranthi Kumar, M. V., Denniff, Matthew, Zukowska-Szczechowska, Ewa, Wagenknecht, Lynne E., Fowkes, F. Gerald R., Charchar, Fadi J., Schwarz, Peter E. H., Hayward, Caroline, Guo, Xiuqing, Rotimi, Charle, Bots, Michiel L., Brand, Eva, Samani, Nilesh J., Polasek, Ozren, Talmud, Philippa J., Nyberg, Fredrik, Kuh, Diana, Laan, Mari, Hveem, Kristian, Palmer, Lyle J., van der Schouw, Yvonne T., Casas, Juan P., Mohlke, Karen L., Vineis, Paolo, Raitakari, Olli, Ganesh, Santhi K., Wong, Tien Y., Shyong Tai, E., Cooper, Richard S., Laakso, Markku, Rao, Dabeeru C., Harris, Tamara B., Morris, Richard W., Dominiczak, Anna F., Kivimaki, Mika, Marmot, Michael G., Miki, Tetsuro, Saleheen, Danish, Chandak, Giriraj R., Coresh, Josef, Navis, Gerjan, Salomaa, Veikko, Han, Bok-Ghee, Zhu, Xiaofeng, Kooner, Jaspal S., Melander, Olle, Ridker, Paul M., Bandinelli, Stefania, Gyllensten, Ulf B., Wright, Alan F., Wilson, James F., Ferrucci, Luigi, Farrall, Martin, Tuomilehto, Jaakko, Pramstaller, Peter P., Elosua, Roberto, Soranzo, Nicole, Sijbrands, Eric J. G., Altshuler, David, Loos, Ruth J. F., Shuldiner, Alan R., Gieger, Christian, Meneton, Pierre, Uitterlinden, Andre G., Wareham, Nicholas J., Gudnason, Vilmundur, Rotter, Jerome I., Rettig, Rainer, Uda, Manuela, Strachan, David P., Witteman, Jacqueline C. M., Hartikainen, Anna-Liisa, Beckmann, Jacques S., Boerwinkle, Eric, Vasan, Ramachandran S., Boehnke, Michael, Larson, Martin G., Järvelin, Marjo-Riitta, Psaty, Bruce M., Abecasis, Gonçalo R., Chakravarti, Aravinda, Elliott, Paul, van Duijn, Cornelia M., Newton-Cheh, Christopher, Levy, Daniel, Caulfield, Mark J., Johnson, Toby, Tang, H, Knowles, J, Hlatky, M, Fortmann, S, Assimes, Tl, Quertermous, T, Go, A, Iribarren, C, Absher, D, Risch, N, Meyers, R, Sidney, S, Ziegler, A, Schillert, A, Bickel, C, Sinning, C, Rupprecht, Hj, Lackner, K, Wild, P, Schnabel, R, Blankenberg, S, Zeller, T, Münzel, T, Perret, C, Cambien, F, Tiret, L, Nicaud, V, Proust, C, Dehghan, A, Hofman, A, Uitterlinden, A, van Duijn, C, Levy, D, Whitteman, J, Cupples, La, Demissie-Banjaw, S, Ramachandran, V, Smith, A, Gudnason, V, Boerwinkle, E, Folsom, A, Morrison, A, Psaty, Bm, Chen, Iy, Rotter, Ji, Bis, J, Volcik, K, Rice, K, Taylor, Kd, Marciante, K, Smith, N, Glazer, N, Heckbert, S, Harris, T, Lumley, T, Kong, A, Thorleifsson, G, Thorgeirsson, G, Holm, H, Gulcher, Jr, Stefansson, K, Andersen, K, Gretarsdottir, S, Thorsteinsdottir, U, Preuss, M, Schreiber, S, Meitinger, T, König, Ir, Lieb, W, Hengstenberg, C, Schunkert, H, Erdmann, J, Fisher, M, Grosshennig, A, Medack, A, Stark, K, Linsel-Nitschke, P, Bruse, P, Aherrahrou, Z, Peters, A, Loley, C, Willenborg, C, Nahrstedt, J, Freyer, J, Gulde, S, Doering, A, Meisinger, C, Wichmann, He, Klopp, N, Illig, T, Meinitzer, A, Tomaschitz, A, Halperin, E, Dobnig, H, Scharnagl, H, Kleber, M, Laaksonen, R, Pilz, S, Grammer, Tb, Stojakovic, T, Renner, W, März, W, Böhm, Bo, Winkelmann, Br, Winkler, K, Hoffmann, M, O'Donnell, Cj, Voight, Bf, Altshuler, D, Siscovick, D, Musunuru, K, Peltonen, L, Barbalic, M, Melander, O, Elosua, R, Kathiresan, S, Schwartz, Sm, Salomaa, V, Guiducci, C, Burtt, N, Gabriel, Sb, Stewart, Af, Wells, Ga, Chen, L, Jarinova, O, Roberts, R, Mcpherson, R, Dandona, S, Pichard, Ad, Rader, Dj, Devaney, J, Lindsay, Jm, Kent, Km, Qu, L, Satler, L, Burnett, M, Li, M, Reilly, Mp, Wilensky, R, Waksman, R, Epstein, S, Mattha, W, Knouf, Cw, Waterworth, Dm, Hakonarson, Hh, Walker, M, Mooser, V, Hall, A, Balmforth, Aj, Wright, Bj, Nelson, C, Thompson, Jr, Samani, Nj, Braund, P, Ball, Sg, Smith, Nl, Felix, Jf, Morrison, Ac, Demissie, S, Glazer, Nl, Loehr, Lr, Rosamond, Wd, Rivadeneira, F, Bis, Jc, Folsom, Ar, Benjamin, E, Aulchenko, Y, Haritunians, T, Couper, D, Murabito, J, Wang, Ya, Stricker, B, Gottdiener, J, Chang, Pp, Wang, Tj, Rice, Km, Heckbert, Sr, Fox, Er, Uitterlinden, Ag, Willerson, Jt, van Duijn, Cm, Witteman, Jc, Vasan, R, Köttgen, A, Pattaro, C, Böger, Ca, Fuchsberger, C, Olden, M, Parsa, A, Gao, X, Yang, Q, Smith, Av, O'Connell, Jr, Schmidt, H, Tanaka, T, Isaacs, A, Ketkar, S, Hwang, Sj, Johnson, A, Teumer, A, Paré, G, Atkinson, Ej, Lohman, K, Cornelis, Mc, Probst-Hensch, Nm, Kronenberg, F, Tönjes, A, Hayward, C, Aspelund, T, Eiriksdottir, G, Launer, Lj, Harris, Tb, Rampersaud, E, Mitchell, Bd, Arking, De, Struchalin, M, Cavalieri, M, Singleton, A, Giallauria, Francesco, Metter, J, de Boer, J, Zillikens, Mc, Oostra, Ba, Feitosa, M, Province, M, de Andrade, M, Turne, St, Schnabel, Rb, Wilde, S, Munzel, Tf, Leak, T, Koenig, W, Zgaga, L, Zemunik, T, Kolcic, I, Minelli, C, Hu, Fb, Johansson, A, Igl, W, Zaboli, G, Wild, Sh, Wright, Af, Campbell, H, Ellinghaus, D, Imboden, M, Nitsch, D, Brandstätter, A, Kollerits, B, Kedenko, L, Mägi, R, Stumvoll, M, Kovacs, P, Boban, M, Campbell, S, Endlich, K, Völzke, H, Kroemer, Hk, Nauck, M, Völker, U, Polasek, O, Vitart, V, Badola, S, Parker, An, Ridker, Pm, Kardia, Sl, Liu, Y, Curhan, Gc, Franke, A, Rochat, T, Paulweber, B, Prokopenko, I, Wang, W, Shuldiner, Ar, Coresh, J, Schmidt, R, Ferrucci, L, Shlipak, Mg, Borecki, I, Krämer, Bk, Rudan, I, Gyllensten, U, Wilson, Jf, Pramstaller, Pp, Rettig, R, Hastie, N, Chasman, Di, Kao, Wh, Heid, Im, Fox, C, Felix, Sb, Watzinger, N, Larson, Mg, Homuth, G, Aragam, J, Dörr, M, Zweiker, R, Lind, L, Rodeheffer, Rj, Greiser, Kh, Deckers, Jw, Stritzke, J, Lackner, Kj, Ingelsson, E, Kullo, I, Haerting, J, Stricker, Bh, Reffelmann, T, Redfield, Mm, Werdan, K, Mitchell, Gf, Arnett, D, Blettner, M, Friedrich, N, Benjamin, Ej, Chambers, Jc, Zhang, W, Lord, Gm, van der Harst, P, Lawlor, Da, Sehmi, J, Gale, Dp, Wass, Mn, Ahmadi, Kr, Bakker, Sj, Beckmann, J, Bilo, Hj, Bochud, M, Brown, Mj, Caulfield, Mj, Connell, Jm, Cook, Ht, Cotlarciuc, I, Davey Smith, G, de Silva, R, Deng, G, Devuyst, O, Dikkeschei, Ld, Dimkovic, T, Dockrell, M, Dominiczak, A, Ebrahim, S, Eggermann, T, Farrall, M, Floege, J, Forouhi, Ng, Gansevoort, Rt, Han, X, Hedblad, B, Homan van der Heide, Jj, Hepkema, Bg, Hernandez-Fuentes, M, Hypponen, E, Johnson, T, de Jong, Pe, Kleefstra, N, Lagou, V, Lapsley, M, Li, Y, Loos, Rj, Luan, J, Luttropp, K, Maréchal, C, Munroe, Pb, Nordfors, L, Penninx, Bw, Perucha, E, Pouta, A, Roderick, Pj, Ruokonen, A, Sanna, S, Schalling, M, Schlessinger, D, Schlieper, G, Seelen, Ma, Sjögren, M, Smit, Jh, Snieder, H, Soranzo, N, Spector, Td, Stenvinkel, P, Sternberg, Mj, Swaminathan, R, Ubink-Veltmaat, Lj, Uda, M, Vollenweider, P, Wallace, C, Waterworth, D, Zerres, K, Waeber, G, Wareham, Nj, Maxwell, Ph, Mccarthy, Mi, Jarvelin, Mr, Abecasis, Gr, Lightstone, L, Scott, J, Navis, G, Elliot, P, and Kooner, Js.
Subjects: novel loci, Kidney Disease, Polymorphism, Single Nucleotide/*genetics, [SDV]Life Sciences [q-bio], left ventricular wall thickness, LOCI, Genome-wide association study, Blood Pressure, Disease, Coronary Artery Disease, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, RELEVANCE, Africa/ethnology, Cardiovascular Disease, genetics, Kidney Diseases/genetics, Stroke, genome wide association study, POPULATION, ta118, Blood pressure, hypertension, stroke, coronary artery disease, ddc:616, 0303 health sciences, education.field_of_study, Asia/ethnology, Multidisciplinary, Coronary Artery Disease/genetics, COMMON VARIANTS, Genetic Predisposition to Disease/*genetics, 3. Good health, Europe, Cardiovascular Diseases, Hypertension, Cardiology, Kidney Diseases, HEALTH, Human, medicine.medical_specialty, Asia, Population, Renal function, Polymorphism, Single Nucleotide, Europe/ethnology, Article, CLONING, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Stroke/genetics, Internal medicine, medicine, Humans, Cardiovascular Diseases/*genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, METAANALYSIS, 030304 developmental biology, RECEPTOR, genes, blood pressure, cardiovascular disease risk, medicine.disease, Africa, Blood Pressure/*genetics/physiology, Hypertension/genetics, Kidney disease, Genome-Wide Association Study
Abstract: Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. ispartof: Nature vol:478 issue:7367 pages:103-109 ispartof: location:England status: published
Published: 2011
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23. Thrombophilic risk factors in the pathogenesis of non-arteritic anterior ischemic optic neuropathy patients

Author: Georgios Kitsos, Konstantinos L. Bourantas, Taxiarchis Felekis, Nikolaos I. Kolaitis, Georgios Vartholomatos, and Ioannis Asproudis
Subjects: Male, medicine.medical_specialty, Hyperlipidemias/genetics/metabolism, Atherosclerosis/genetics/metabolism, Blood Proteins/genetics/metabolism, Hyperlipidemias, Thrombophilia, Pathogenesis, Cellular and Molecular Neuroscience, Thrombophilia/*epidemiology/genetics/metabolism, Risk Factors, medicine.artery, Internal medicine, Ischemic infarction, medicine, Humans, Optic Neuropathy, Ischemic, Prospective Studies, Aged, Aged, 80 and over, Polymorphism, Genetic, business.industry, Oxidoreductases/genetics/metabolism, Blood Proteins, Middle Aged, Atherosclerosis, medicine.disease, Sensory Systems, Ciliary arteries, Surgery, Arteritic anterior ischemic optic neuropathy, Ophthalmology, Increased risk, Hypertension, Cardiology, Optic nerve, Anterior ischemic optic neuropathy, Female, Oxidoreductases, business, Hypertension/genetics, Optic Neuropathy, Ischemic/*etiology/genetics/metabolism
Abstract: BACKGROUND: Non-arteritic anterior ischemic optic neuropathy (N-AION) is caused by acute ischemic infarction of the optic nerve head, supplied by the posterior ciliary arteries. Thrombophilia is the tendency/predisposition to vascular thromboses of arteries and veins, and the existence of thrombophilic risk factors leads to blood hypercoagulability and potentially increased risk for thromboses. OBJECTIVES: To investigate whether there is an association between N-AION and a wide spectrum of thrombophilic risk factors. PATIENTS AND METHODS: Seventy-seven consecutive cases of confirmed N-AION and 60 age- and sex-matched consecutive controls constituted the study group. Fibrinogen levels, deficiency of proteins C, S, ATIII, lupus anticoagulant, activated protein C resistance, factor V Leiden, factor V H1299R, factor II G20210A, MTHFR C677T, MTHFR A1298C, GPIIIa A1/A2, and ACE I/D polymorphisms were analysed. RESULTS: Statistical analysis of the plasma proteins in our study demonstrated that the only significant difference was the one concerning protein S levels. In particular, the mean value for N-AION patients was 78.8% +/- 21.2, and for the control group the mean value was 88% +/- 21.2 (p = 0.013). Despite the above-mentioned result, there was not any statistical difference between the two subgroups regarding actual protein S deficiency, as 9/77 (11.7%) patients and 4/60 (6.7%) controls had protein S levels below 60% (p = 0.32). In our study sample, homozygosity for MTHFR C677T polymorphism in the study group as a whole, and the presence of at least one A2 allele of GPIIIa in the subgroup of male patients as compared to healthy male controls, proved to be the most significant thrombophilic risk factors, with odds ratios of 16.78 (95% C.I 0.96-294.42, p = 0.054) and 4.6 (95% C.I 1.52-13.88, p = 0.007) respectively. CONCLUSION: Screening for these polymorphisms would probably constitute a valuable procedure in N-AION patients, as they may have an important contribution to the pathogenesis of the disease. Graefes Arch Clin Exp Ophthalmol
Published: 2010
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24. Implication of chromosome 13 on hypertension and associated disorders in Lyon hypertensive rats

Author: Anne E. Kwitek, Alain Bataillard, Juerg Nussberger, Sophie Gilibert, and Jean Sassard
Subjects: Male, medicine.medical_specialty, Physiology, Quantitative Trait Loci, Congenic, Blood Pressure, Quantitative trait locus, Biology, Kidney, Plasma renin activity, Article, Animals, Congenic, Risk Factors, Rats, Inbred BN, Rats, Inbred SHR, Internal medicine, Renin, Hyperlipidemia, Internal Medicine, medicine, Animals, Humans, Blood Pressure/genetics, Cardiovascular Diseases/etiology, Chromosome Mapping, Disease Models, Animal, Hypertension/genetics, Hypertension/physiopathology, Kidney/physiopathology, Rats, Rats, Inbred SHR/genetics, Rats, Inbred SHR/physiology, Renin/blood, Chromosome 13, Proteinuria, medicine.disease, medicine.anatomical_structure, Endocrinology, Blood pressure, Cardiovascular Diseases, Hypertension, medicine.symptom, Cardiology and Cardiovascular Medicine
Abstract: Background Hypertension and associated disorders are major risk factors for cardiovascular disease. The Lyon hypertensive rat (LH) is a genetically hypertensive strain that exhibits spontaneous and salt-sensitive hypertension, exaggerated proteinuria, high body weight, hyperlipidemia, and elevated insulin-to-glucose ratio. Previous genetic mapping identified quantitative trait loci (QTLs) influencing blood pressure (BP) on rat chromosome 13 (RN013) in several models of hypertension. Methods To study the effects of a single chromosome on the mapped traits, we generated consomic strains by substituting LH RNO13 with that of the normotensive Brown Norway (BN) strain (LH-13 BN ) and reciprocal consomics by substituting a BN RNO13 with that of LH (BN-13 LH ). These reciprocal consomic strains, as well as the two parental strains were characterized for BP, metabolic and morphological parameters. Results Compared with LH parents, LH-13 BN rats showed decreased mean BP (up to ―24 mmHg on 2% NaCl in the drinking water), urine proteins and lipids, and increased body weight. Differences between BN-13 LH and BN rats were much smaller than those observed between LH-13 BN and LH rats, demonstrating the effects of the highly resistant BN genome background. Plasma renin activity was not affected by the substitution of RN013, despite the significant BP differences. Conclusion The present work demonstrates that RNO13 is a determinant of BP, proteinuria, and plasma lipids in the LH rat. The distinct phenotypic differences between the consomic LH-13 BN and the LH make it a powerful model to determine genes and pathways leading to these risk factors for cardiovascular and renal disease.
Published: 2009
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25. Heritability and intrafamilial aggregation of arterial characteristics

Author: Jitka Seidlerová, Bochud, Murielle, Staessen, Jan A., Cwynar, Marcin, Dolejsova, Milena, Kuznetsova, Tatiana, Nawrot, Tim, Olszanecka, Agnieszka, Stolarz, Katarzyna, Thijs, Lutgarde, Wojciechowska, Wiktoria, Struijker-Boudier, Harry A., Kawecka-Jaszcz, Kalina, Elston, Robert C., Fagard, Robert, Filipovsky, Jan, and Epogh, Investigators
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Brachial Artery, Population sample, Physiology, Blood Pressure, Environment, 030204 cardiovascular system & hematology, Aged, Aorta/physiology, Arteries/physiology, Belgium, Blood Pressure/genetics, Brachial Artery/physiology, Czech Republic, Family, Female, Humans, Hypertension/genetics, Hypertension/physiopathology, Middle Aged, Phenotype, Poland, Pulsatile Flow/physiology, Radial Artery/physiology, Article, Correlation, 03 medical and health sciences, 0302 clinical medicine, Internal Medicine, Medicine, 030212 general & internal medicine, Agrégation, Aorta, Genetics, business.industry, Family aggregation, Arteries, Heritability, medicine.disease, Pulsatile Flow, Hypertension, Radial Artery, Arterial stiffness, Cardiology and Cardiovascular Medicine, business
Abstract: BACKGROUND: We investigated the heritability and familial aggregation of various indexes of arterial stiffness and wave reflection and we partitioned the phenotypic correlation between these traits into shared genetic and environmental components. METHODS: Using a family-based population sample, we recruited 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years) from the population in Cracow, Poland (62 families), Hechtel-Eksel, Belgium (36), and Pilsen, the Czech Republic (50). We measured peripheral pulse pressure (PPp) sphygmomanometrically at the brachial artery; central pulse pressure (PPc), the peripheral augmentation indexes (PAIxs) and central augmentation indexes (CAIxs) by applanation tonometry at the radial artery; and aortic pulse wave velocity (PWV) by tonometry or ultrasound. In multivariate-adjusted analyses, we used the ASSOC and PROC GENMOD procedures as implemented in SAGE and SAS, respectively. RESULTS: We found significant heritability for PAIx, CAIx, PPc and mean arterial pressure ranging from 0.37 to 0.41; P < or = 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r > or = 0.12; P < or = 0.02) with the exception of PPc (r = -0.007; P = 0.90) in parent-offspring pairs. The sib-sib correlations were also significant for CAIx (r = 0.22; P = 0.001). The genetic correlation between PWV and the other arterial indexes were significant (rhoG > or = 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (rhoE = 0.10, P = 0.03). CONCLUSION: The observation of significant intrafamilial concordance and heritability of various indexes of arterial stiffness as well as the genetic correlations among arterial phenotypes strongly support the search for shared genetic determinants underlying these traits. ispartof: Journal of Hypertension vol:26 issue:4 pages:721-728 ispartof: location:Netherlands status: published
Published: 2008
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26. Telomere dysfunction in hypertension

Author: Javier Díez, Vicente Andrés, and José J. Fuster
Subjects: Genome instability, Senescence, Aging, medicine.medical_specialty, Telomerase, Heart disease, Physiology, Blood Pressure, Disease, Endothelin-Converting Enzymes, Biology, Bioinformatics, medicine.disease_cause, Muscle, Smooth, Vascular, Pathogenesis, Internal medicine, Leukocytes, Internal Medicine, medicine, Aspartic Acid Endopeptidases, Humans, Telomeric Repeat Binding Protein 2, Metalloendopeptidases, Nuclear Proteins, Telomere, medicine.disease, Oxidative Stress, Endocrinology, Hypertension, TATA Box Binding Protein-Like Proteins, Cardiology and Cardiovascular Medicine, Hypertension/genetics, Oxidative stress
Abstract: 8 páginas, 2 figuras.-- El documento en word es la versión post-print., Aging is a major risk factor for hypertension and associated cardiovascular disease. In most proliferative tissues, aging is characterized by shortening of the DNA component of telomeres, the specialized genetic segments that cap the end of eukaryotic chromosomes and protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, telomere shortening is thought to contribute to organismal aging and to the development of age-related diseases. Here, we review animal and human studies that have investigated the possible links between telomere ablation and the pathogenesis of hypertension and related target organ damage. Although evidence is mounting that alterations in telomerase activity and telomere shortening may play a role in the pathogenesis of hypertension, additional studies are required to understand the molecular mechanisms by which telomere dysfunction and hypertension are functionally connected. As our knowledge on this emerging field grows, the challenge will be to ascertain whether all this information might translate into clinical applications., Work in the author’s laboratories is partly supported by grants from Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Red Temática de Investigación Cooperativa Cardiovascular RECAVA), and from the Ministerio de Educación y Ciencia and the European Regional Development Fund (SAF2004-03057). J.J.F. is supported by a CSIC-I3P predoctoral fellowship co-sponsored by the European Social Fund.
Published: 2007
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27. AT(2) Receptor and Tissue Injury: Therapeutic Implications

Author: Ulrike Muscha Steckelings, Chiara Recarti, Pawel Namsolleck, Sébastien Foulquier, Thomas Unger, Pathologie, Bedrijfsbureau CD, RS: CARIM - R3 - Vascular biology, and Cardiologie
Subjects: Nervous system, Apoptosis, Cardioprotection, AT2 receptor, Bioinformatics, Proto-Oncogene Mas, Brain ischemia, Fibrosis, Signal Transduction/drug effects, Medicine, Aortic aneurysm, Angiotensin II, Receptor, Angiotensin, Type 2/agonists, Neuroprotection, Stroke, medicine.anatomical_structure, Growth promotion/inhibition, Hypertension, Neuroregeneration, Renin-angiotensin system, Signal Transduction, CGP42112, PD123319, Spinal cord injury, Receptor, Angiotensin, Type 2, Receptor, Angiotensin, Type 1, Receptor, Angiotensin, Type 1/metabolism, Vascular protection, Internal Medicine, Animals, Humans, Renin-Angiotensin System/genetics, AT receptor, Mediators, Mechanisms, and Pathways in Tissue Injury (T Fujita, Section Editor), Inflammation, Angiotensin II receptor type 1, business.industry, medicine.disease, Tissue injury, Atherosclerosis, Signaling, Disease Models, Animal, Myocardial infarction, AT(2) receptor, Immunology, business, Hypertension/genetics
Abstract: The renin-angiotensin system (RAS) plays an important role in the initiation and progression of tissue injuries in the cardiovascular and nervous systems. The detrimental actions of the AT(1) receptor (AT(1)R) in hypertension and vascular injury, myocardial infarction and brain ischemia are well established. In the past twenty years, protective actions of the RAS, not only in the cardiovascular, but also in the nervous system, have been demonstrated. The so-called protective arm of the RAS includes AT(2)-receptors and Mas receptors (AT(2)R and MasR) and is characterized by effects different from and often opposing those of the AT(1)R. These include anti-inflammation, anti-fibrosis, anti-apoptosis and neuroregeneration that can counterbalance pathological processes and enable recovery from disease. The recent development of novel, small-molecule AT(2)R agonists offers a therapeutic potential in humans with a variety of clinical indications.
Published: 2014
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28. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

Author: Doris Lechner, Miriam Capri, Stefan Böhringer, Stefan Schreiber, Gonneke Willemsen, Paolo Garagnani, Irene Maeve Rea, Andres Metspalu, Palmi V. Jonsson, Thomas B. L. Kirkwood, Lene Christiansen, Fernando Rivadeneira, Giuseppina Rose, J. Wouter Jukema, Serena Dato, Owen A. Ross, Almut Nebel, Cornelia M. van Duijn, Gary Saunders, Bernard Jeune, David J. Stott, Jeanine J. Houwing-Duistermaat, A. Murphy, Anton J. M. de Craen, Friederike Flachsbart, Karen Andersen-Ranberg, Albert Hofman, Ian Ford, Ellen A. Nohr, Giuseppe Passarino, Krista Fischer, Elisa Cevenini, Carmen Martin-Ruiz, Jutta Gampe, Iris Postmus, Christopher P. Nelson, Stefano Salvioli, Alberto Montesanto, Mark Lathrop, Marianne Nygaard, Marie E. Breen, Jennifer Harrow, Hae-Won Uh, Erik B. van den Akker, Thorkild I. A. Sørensen, André G. Uitterlinden, Alexander Viktorin, Bastiaan T. Heijmans, Susan E. McNerlan, Quinta Helmer, Naveed Sattar, Claudio Franceschi, Eco J. C. de Geus, E. Mihailov, Jouke-Jan Hottenga, Qihua Tan, Kari Stefansson, Yoichiro Kamatani, Paolina Crocco, Henning Tiemeier, Stella Trompet, Patrik K. E. Magnusson, Marian Beekman, Riin Tamm, Amke Caliebe, Maris Alver, Femke-Anouska Heinsen, Pilar Galan, Daníel F. Guðbjartsson, Joris Deelen, Linda Broer, Ruud van der Breggen, Kristin L. Ayers, Anna M. Bennet, Dorret I. Boomsma, P. Eline Slagboom, Kaare Christensen, Diana van Heemst, Joanna Collerton, Karen Davies, Rudi G. J. Westendorp, Hélène Blanché, Lavinia Paternoster, Nilesh J. Samani, Hreinn Stefansson, Simon P. Mooijaart, Heather J. Cordell, Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), LeidenUniversity Medical Centre, Department of Epidemiology, The Netherlands Cancer Institute, Institute of Genetic Medicine, Newcastle University [Newcastle], National Institute of Public Health, University of Southern Denmark (SDU), Department of Clinical Genetics, Odense University Hospital, Fondation Jean Dausset - Centre d’Étude du Polymorphisme Humain, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Tartu, Institute of Molecular and Cell Biology, Department of Gerontology and Geriatrics, Leiden University Medical Center (LUMC), deCODE genetics [Reykjavik], Christian-Albrechts University of Kiel, University of Calabria, Delft University of Technology (TU Delft), Department of Cardiovascular Sciences, Université Catholique de Louvain = Catholic University of Louvain (UCL), University Hospitals Leicester, Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], School of Medicine, Dentistry and Biomedical Sciences [Belfast], Queen's University [Belfast] (QUB), University of Iowa [Iowa City], DIMES: Department of Experimental, Diagnostic and Specialty Medicine, Bologna University Hospital, Institute for Ageing and Health, University of Glasgow, Max Planck Institute for Demographic Research (MPIDR), Max-Planck-Gesellschaft, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO Institute for Health and Care Research, VU University Amsterdam Medical Center, Landspitali National University Hospital of Iceland, University of Iceland, McGill University = Université McGill [Montréal, Canada], Genome Quebec Innovation Centre, Institut de Génomique, Belfast Health and Social Care Trust, Estonian Biocentre, Partenaires INRAE, Aarhus University [Aarhus], School of Social and Community Medicine, Erasmus University Rotterdam, Mayo Clinic, BHF Glasgow Cardiovascular Research Centre, University Medical Center Schleswig-Holstein, Institute of Cardiovascular and Medical Sciences, Sophia Children's Hospital, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Augustinus Foundation, Avera Institute for Human Genetics (AIHG), AXA Research Fund, Belfast City Hospital Trust Fund, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI -NL) [184.021.007], Biotechnology and Biological Sciences Research Council (BBSRC), Bristol-Myers Squibb, Center for Inherited Disease Research (CIDR), Centre for Medical Systems Biology (CMSB), CERA Foundation, Commissariat a L'Energie Atomique (CEA)-Centre National de Genotypage (CNG), Danish Agency for Science, Technology and Innovation (DASTI)/The Danish Council for Independent Research (DCIR) [11-107308], Danish National Research Foundation (DNRF), Department of Health and Social Services (Northern Ireland), DFG-Cluster of Excellence 'Inflammation at Interfaces', Dunhill Medical Trust [R124/0509], Egmont Foundation, Estonian Science Foundation [7859], Estonian Government [SF0180142s08], European Research Council (ERC) [230374], European Science Foundation (ESF) [EU/QLRT-2001-01254], European Union [FP5-QLK6-CY-2001-00128, FP6-LIFESCIHEALTH-36894, FP6-LSH M-CT-2004-503270, FP7-HEALTH-2007-B-223004, FP7-HEALTH-F4-2007-201413, FP7-HEALTH-F4-2008-202047, FP7-HEALTH-2009-single-stage-242244, FP7-HEALTH-2010-two-stage-259679], Fondation Caisse d'Epargne Rhone-Alpes Lyon CERAL, Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health (NIMH) [MH081802], GenomEUtwin [EU/QLRT-2001-01254, QLG2-CT-2002-01254], Guy's & St Thomas' NHS Foundation Trust, Health Foundation, Heart and Lung foundation [20070481], Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE05007], Institut National de la Recherche Agronomique (INRA), Institut National de la Sante et de la Recherche Medicale (INSERM), King's College London, Medical Research Council (MRC) [G0500997, G0601333], Ministere de l'Enseignement superieur et de la Recherche (MESR), National Institutes of Health (NIH)/National Institute of Aging (NIA) [P01AG08761, R01D0042157-01A, U01DK066134], National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre, NBIC BioAssist [NWO-NBIC/BioAssist/RK/2008.024], Netherlands Consortium for Healthy Ageing (NCHA) [050-060-810], Netherlands Genomics Initiative (NGI), Netherlands Heart Foundation (NHF) [2001 D 032], Netherlands Organization for Scientific Research (NWO, MagW/ZonMW) [904-61-090, 904-61-193, 480-04-004, 400-05-717, Spinozapremie 56-464-14192, 175.010.2005.011, 911-03-012, 985-10-002, Addiction-31160008, Middelg-root-911-09-032], Netspar - Living longer for a good health, NHS North of Tyne (Newcastle Primary Care Trust), Pharmacy Foundation, Regione Autonoma della Sardegna, Rutgers University Cell and DNA Repository [NIMH U24 MH068457-06], Swedish Research Council [M-2005-1112], Tampere University Hospital and Academy of Finland, Danish Interdisciplinary Research Council, Health Foundation (Helsefonden), Ministry for Higher Education, National Program for Research Infrastructure [09-063256], March of Dimes Birth Defects Foundation, Swedish Foundation for Strategic Research (SSF), Unilever Discover Colworth, Universite Paris 13, University of Tartu [SP1GVAR-ENG], Velux Foundation, VU University's Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA), Wellcome Trust [084762, 085475, 087436], IDEAL [FP7-HEALTH-2010-two-stage-259679], Research and Education into Ageing-0153, European Regional Development Fund, Deelen J, Beekman M, Uh HW, Broer L, Ayers KL, Tan Q, Kamatani Y, Bennet AM, Tamm R, Trompet S, Guðbjartsson DF, Flachsbart F, Rose G, Viktorin A, Fischer K, Nygaard M, Cordell HJ, Crocco P, van den Akker EB, Böhringer S, Helmer Q, Nelson CP, Saunders GI, Alver M, Andersen-Ranberg K, Breen ME, van der Breggen R, Caliebe A, Capri M, Cevenini E, Collerton JC, Dato S, Davies K, Ford I, Gampe J, Garagnani P, de Geus EJ, Harrow J, van Heemst D, Heijmans BT, Heinsen FA, Hottenga JJ, Hofman A, Jeune B, Jonsson PV, Lathrop M, Lechner D, Martin-Ruiz C, McNerlan SE, Mihailov E, Montesanto A, Mooijaart SP, Murphy A, Nohr EA, Paternoster L, Postmus I, Rivadeneira F, Ross OA, Salvioli S, Sattar N, Schreiber S, Stefánsson H, Stott DJ, Tiemeier H, Uitterlinden AG, Westendorp RG, Willemsen G, Samani NJ, Galan P, Sørensen TI, Boomsma DI, Jukema JW, Rea IM, Passarino G, de Craen AJ, Christensen K, Nebel A, Stefánsson K, Metspalu A, Magnusson P, Blanché H, Christiansen L, Kirkwood TB, van Duijn CM, Franceschi C, Houwing-Duistermaat JJ, Slagboom PE., Leiden Univ, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands [ 2 ] Leiden Univ, Netherlands Consortium Healthy Ageing, NL-2300 RC Leiden, Netherlands [ 3 ] Leiden Univ, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands [ 4 ] Leiden Univ, Dept Cardiol, NL-2300 RC Leiden, Netherlands [ 5 ] Leiden Univ, Dept Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands [ 6 ] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands [ 7 ] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands [ 8 ] Newcastle Univ, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England [ 9 ] Univ So Denmark, Inst Publ Hlth, DK-5000 Odense C, Denmark [ 10 ] Univ So Denmark, Inst Clin Res, Dept Gynecol & Obstet, DK-5000 Odense C, Denmark [ 11 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 12 ] Odense Univ Hosp, Clin Biochem & Pharmacol, DK-5000 Odense C, Denmark [ 13 ] Fdn Jean Dausset CEPH, F-75010 Paris, France [ 14 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 15 ] Univ Tartu, Estonian Genome Ctr, Tartu 51010, Estonia [ 16 ] Univ Tartu, Inst Mol & Cell Biol, EE-51010 Tartu, Estonia [ 17 ] deCODE Genet, Populat Gen, IS-101 Reykjavik, Iceland [ 18 ] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany [ 19 ] Univ Kiel, Inst Med Informat & Stat, D-24105 Kiel, Germany [ 20 ] Univ Calabria, Dept Biol Ecol & Earth Sci, I-87036 Arcavacata Di Rende, Italy [ 21 ] Delft Univ Technol, Delft Bioinformat Lab, NL-2600 GA Delft, Netherlands [ 22 ] Univ Leicester, Dept Cardiovasc Sci, Leicester LE3 9QP, Leics, England [ 23 ] Glenfield Hosp, Cardiovasc Biomed Res Unit, Natl Inst Hlth Res, Leicester LE3 9QP, Leics, England [ 24 ] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England [ 25 ] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Belfast BT9 7BL, Antrim, North Ireland [ 26 ] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA [ 27 ] Univ Bologna, Dept Expt Diagnost & Specialty Med, I-40126 Bologna, Italy [ 28 ] Univ Bologna, Interdepartmental Ctr L Galvani, I-40126 Bologna, Italy [ 29 ] Newcastle Univ, Inst Ageing & Hlth, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England [ 30 ] Univ Glasgow, Robertson Ctr Biostat, Glasgow G12 8QQ, Lanark, Scotland [ 31 ] Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow G12 8QQ, Lanark, Scotland [ 32 ] Max Planck Inst Demograf Forsch, Lab Stat Demog, D-18057 Rostock, Germany [ 33 ] Vrije Univ Amsterdam, Dept Biol Psychol, NL-1081 BT Amsterdam, Netherlands [ 34 ] Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, NL-1081 BT Amsterdam, Netherlands [ 35 ] Landspitali Univ Hosp, IS-101 Reykjavik, Iceland [ 36 ] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland [ 37 ] CEA, Inst Genom, F-91057 Evry, France [ 38 ] McGill Univ, Montreal, PQ H3G 1A4, Canada [ 39 ] Genome Quebec Innovat Ctr, Montreal, PQ H3G 1A4, Canada [ 40 ] Belfast Hlth & Social Care Trust, Cytogenet Lab, Belfast BT8 8BH, Antrim, North Ireland [ 41 ] Estonian Bioctr, EE-51010 Tartu, Estonia [ 42 ] Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, DK-8000 Aarhus C, Denmark [ 43 ] Univ Bristol, Sch Social & Community Med, MRC Ctr Causal Anal Translat Epidemiol, Bristol BS8 2BN, Avon, England [ 44 ] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA [ 45 ] Univ Glasgow, Fac Med, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland [ 46 ] Univ Kiel, PopGen Biobank, D-24105 Kiel, Germany [ 47 ] Univ Hosp Schleswig Holstein, D-24105 Kiel, Germany [ 48 ] Sophia Childrens Univ Hosp, Erasmus Med Ctr, Dept Child & Adolescent Psychiat, NL-3000 CA Rotterdam, Netherlands [ 49 ] Univ Paris 04, UREN, U557, INSERM, F-93017 Bobigny, France [ 50 ] U1125 Inra, F-93017 Bobigny, France [ 51 ] Cnam, F-93017 Bobigny, France [ 52 ] Univ Paris 13, CRNH IdF, F-93017 Bobigny, France [ 53 ] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr, DK-2200 Copenhagen N, Denmark [ 54 ] Inst Prevent Med, DK-2000 Copenhagen, Denmark [ 55 ] Frederiksberg Univ Hosp, DK-2000 Copenhagen, Denmark [ 56 ] Interuniv Cardiol Inst Netherlands, NL-3501 DG Utrecht, Netherlands [ 57 ] Bellaria Hosp, IRCCS Inst Neurol Sci, I-40139 Bologna, Italy [ 58 ] CNR, ISOF, I-40129 Bologna, Italy, Epidemiology, Surgery, Internal Medicine, Child and Adolescent Psychiatry / Psychology, ProdInra, Migration, Vrije Universiteit Amsterdam [Amsterdam] (VU), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), VU University Amsterdam, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes
Subjects: Male, Netherlands Twin Register (NTR), Disease/genetics, Lífslíkur, Longevity/genetics, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetic Linkage, Genome-wide association study, 0302 clinical medicine, Prospective Studies, Genetics (clinical), Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Association Studies Articles, Age Factors, Chromosome Mapping, Genetic Loci/physiology, General Medicine, 3. Good health, Europe, Phenotype, Cardiovascular Diseases, Hypertension, Chromosomes, Human, Pair 5, Female, Human Longevity, genetics, meta-analysis, Aging/genetics, Cardiology and Cardiovascular Medicine, HUMAN AGING, Longevity, European Continental Ancestry Group, Population, HUMAN GENETICS, Single-nucleotide polymorphism, Locus (genetics), Biology, FAMILIAL LONGEVITY, White People, 03 medical and health sciences, Gene mapping, SDG 3 - Good Health and Well-being, Cardiovascular Diseases/genetics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Allele, education, Molecular Biology, Aged, 030304 developmental biology, Genetic association, Öldrun, Genome, Human, Arfgengi, Minor allele frequency, Ageing, Genetic Loci, Chromosomes, Human, Pair 19, Hypertension/genetics, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (
Published: 2014
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29. Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Author: Caroline Ronzaud, Natasha A. Boase, Johannes Loffing, Baoli Yang, Romain Perrier, Nicole Fowler-Jaeger, Edith Hummler, Dominique Loffing-Cueni, Sumedha Malsure, Marc Maillard, Sharad Kumar, Pierrette Hausel, Olivier Staub, Robert Koesters, Anne Debonneville, John B. Stokes, Ronzaud, Caroline, Loffing-Cueni, Dominique, Hausel, Pierrette, Debonneville, Anne, Malsure, Sumedha Ram, Fowler-Jaeger, Nicole, Boase, Natasha Anne, Perrier, Romain, Maillard, Marc, Yang, Baoli, Stokes, John B, Koesters, Robert, Kumar, Sharad, Hummler, Edith, Loffing, Johannes, Staub, Olivier, and University of Zurich
Subjects: Epithelial sodium channel, 10017 Institute of Anatomy, Animals, Blood Pressure, Disease Models, Animal, Endosomal Sorting Complexes Required for Transport/deficiency, Endosomal Sorting Complexes Required for Transport/genetics, Epithelial Sodium Channels/metabolism, Humans, Hypertension/etiology, Hypertension/genetics, Kidney Tubules/physiopathology, Liddle Syndrome/etiology, Liddle Syndrome/genetics, Mice, Mice, Knockout, Potassium/blood, Potassium/urine, Potassium Channels, Inwardly Rectifying/metabolism, Receptors, Drug/metabolism, Sodium/blood, Sodium/urine, Sodium, Dietary/administration & dosage, Sodium, Dietary/adverse effects, Symporters/metabolism, Ubiquitin-Protein Ligases/deficiency, Ubiquitin-Protein Ligases/genetics, Nedd4 Ubiquitin Protein Ligases, Receptors, Drug, knockout, 2700 General Medicine, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Solute Carrier Family 12, Member 3, humans, 0303 health sciences, Aldosterone, Symporters, Chemistry, General Medicine, animals, Kidney Tubules, kidney tubules, Hypertension, Research Article, medicine.medical_specialty, mice, hypertension, Ubiquitin-Protein Ligases, 610 Medicine & health, macromolecular substances, 03 medical and health sciences, Liddle Syndrome, Internal medicine, medicine, Potassium Channels, Inwardly Rectifying, Epithelial Sodium Channels, 030304 developmental biology, NEDD4L, disease models, Endosomal Sorting Complexes Required for Transport, urogenital system, Sodium, Sodium, Dietary, Endocrinology, Symporter, Potassium, Commentary, ROMK, 570 Life sciences, biology, Cotransporter, Homeostasis
Abstract: The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high- Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK. Refereed/Peer-reviewed
Published: 2013

30. Integrated computational and experimental analysis of the neuroendocrine transcriptome in genetic hypertension identifies novel control points for the cardiometabolic syndrome

Author: Georg Ehret, Ryan S. Friese, Geert W. Schmid-Schönbein, Chun Ye, Daniel T. O'Connor, Fangwen Rao, Patricia B. Munroe, Jill Waalen, Eleazar Eskin, Nitish R. Mahapatra, Philip S Napolitan, Andrew J. Schork, and Caroline M. Nievergelt
Subjects: Male, systolic blood pressure, Transcription, Genetic, genotype, complementary DNA, Blood Pressure, Cardiovascular, Transcriptome, Mice, 0302 clinical medicine, Adrenal Glands/metabolism, Transcriptional Activation/genetics, Aetiology, Oligonucleotide Array Sequence Analysis, ddc:616, transcription factor YY1, 0303 health sciences, education.field_of_study, gene expression regulation, luciferase, Transcriptome/genetics, reporter gene, 3. Good health, Myocardium/metabolism/pathology, priority journal, complex trait, mouse strain, transcription regulation, Cardiology and Cardiovascular Medicine, Transcriptional Activation, Blood Pressure/genetics, Enhancer Elements, RNA, Messenger/genetics/metabolism, Molecular Sequence Data, human genetics, Single-nucleotide polymorphism, Luciferases/metabolism, Article, Protein Binding/genetics, 03 medical and health sciences, Genetic, Genetics, Humans, human, RNA, Messenger, education, mouse, adrenal gland, animal model, Myocardium, diastolic blood pressure, Computational Biology, DNA, Computational Biology/methods, medicine.disease, Promoter Regions, Genetic/genetics, BPH mouse strain, Neurosecretory Systems, Human genetics, glucose blood level, Blood pressure, microarray analysis, Metabolic syndrome, Transcription Factors, Candidate gene, Messenger, Medical Biotechnology, Metabolic Syndrome X/genetics, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Essential hypertension, single nucleotide polymorphism, Adrenal Glands, 2.1 Biological and endogenous factors, Luciferases, Promoter Regions, Genetic, Genetics (clinical), 2. Zero hunger, Metabolic Syndrome, screening and diagnosis, Metabolic Syndrome X, Nucleotide Motifs/genetics, Detection, Enhancer Elements, Genetic, essential (genetic) hypertension, Hypertension, Neurosecretory Systems/metabolism, computer analysis, Transcription, Biotechnology, Protein Binding, animal experiment, Population, Biology, metabolic syndrome, Promoter Regions, promoter region, Meta-Analysis as Topic, medicine, Animalia, Animals, controlled study, Transcription Factors/metabolism, Genetic Predisposition to Disease, Obesity, Nucleotide Motifs, protein motif, Metabolic and endocrine, Nutrition, 030304 developmental biology, algorithm, nonhuman, Base Sequence, Enhancer Elements, Genetic/genetics, Human Genome, essential hypertension, population genetics, prediction, body mass, 4.1 Discovery and preclinical testing of markers and technologies, Cardiovascular System & Hematology, RNA, Hypertension/genetics
Abstract: Background— Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists betweens the fraction of population trait variance explained by such associations and total disease heritability. Methods and Results— We developed a novel, integrative method (combining animal models, transcriptomics, bioinformatics, molecular biology, and trait-extreme phenotypes) to identify candidate genes for essential hypertension and the metabolic syndrome. We first undertook transcriptome profiling on adrenal glands from blood pressure extreme mouse strains: the hypertensive BPH (blood pressure high) and hypotensive BPL (blood pressure low). Microarray data clustering revealed a striking pattern of global underexpression of intermediary metabolism transcripts in BPH. The MITRA algorithm identified a conserved motif in the transcriptional regulatory regions of the underexpressed metabolic genes, and we then hypothesized that regulation through this motif contributed to the global underexpression. Luciferase reporter assays demonstrated transcriptional activity of the motif through transcription factors HOXA3, SRY, and YY1. We finally hypothesized that genetic variation at HOXA3 , SRY , and YY1 might predict blood pressure and other metabolic syndrome traits in humans. Tagging variants for each locus were associated with blood pressure in a human population blood pressure extreme sample with the most extensive associations for YY1 tagging single nucleotide polymorphism rs11625658 on systolic blood pressure, diastolic blood pressure, body mass index, and fasting glucose. Meta-analysis extended the YY1 results into 2 additional large population samples with significant effects preserved on diastolic blood pressure, body mass index, and fasting glucose. Conclusions— The results outline an innovative, systematic approach to the genetic pathogenesis of complex cardiovascular disease traits and point to transcription factor YY1 as a potential candidate gene involved in essential hypertension and the cardiometabolic syndrome.
Published: 2012

31. Blood Pressure Loci Identified with a Gene-Centric Array

Author: Meena Kumari, Claire E. Hastie, Jonathan Stephens, Patricia B. Munroe, Christopher P. Nelson, John M. C. Connell, Martin D. Tobin, Hani Neuvrith, Jean Tichet, Paul Burton, Gudrun Veldre, Daniele Cusi, Anna Levinsson, Paul Elliott, Elin Org, Erika Salvi, Tina Shah, Nabila Devos, Harm-Jan Westra, Juan-Pablo Casas, Olle Melander, Jan A. Staessen, Nilesh J. Samani, Jackie A. Cooper, Peter S. Braund, Neil R Poulter, Alive V. Stanton, Abiodun Onipinla, Marcel G. M. Wolfs, Steve E. Humphries, Philippa J. Talmud, Rebecca Hardy, Fotios Drenos, Maris Laan, Mark J. Caulfield, Richard Dobson, Willem H. Ouwehand, Yun Zhang, Li Chen, SG Wannamethee, Sue Shaw-Hawkins, Christopher Newton-Cheh, Eoin O'Brien, Simon A. McG. Thom, Maria Grazia Franzosi, Charles A. Mein, Mika Kivimäki, Tom R. Gaunt, Jennifer G. Sambrook, Andrea Stucchi, Annika Rosengren, Sonia Shah, Thomas Hedner, George A. Wells, Dag S. Thelle, Debbie A Lawlor, Pierre-François Plouin, Fredrik Nyberg, Richard W Morris, Ian N M Day, Vesela Gateva, Lude Franke, Peter S. Sever, Morris J. Brown, Margus Putku, Sandosh Padmanabhan, John F. Peden, Pim van der Harst, Jutta Palmen, Ioanna Tzoulaki, Alexandre F.R. Stewart, Andrew Wong, Peeter Juhanson, Marciej Tomaszewski, Alison H. Goodall, Martin Farrall, Wai K. Lee, Nicola Glorioso, Hugh Watkins, Xavier Jeunemaitre, Anders Hamsten, Robert Clarke, Anna F. Dominiczak, Mark Lathrop, Stephen Newhouse, Margus Viigimaa, George Davey Smith, Robert Roberts, John C. Whittaker, Michael V. Holmes, Toby Johnson, F. Gerald R. Fowkes, Aroon D. Hingorani, Udo Seedorf, Siim Sõber, Denis C. Shields, Diana Kuh, Chris Wallace, Philip Howard, Peter H. Whincup, Gonçalo R. Abecasis, Anuj Goel, Christian Delles, Björn Wahlstrand, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiogenics Consortium, Global BPgen Consortium, Newton-Cheh, C., Johnson, T., Gateva, V., Tobin, M.D., Bochud, M., Coin, L., Najjar, S.S., Hua, J., Heath, S.C., Eyheramendy, S., Papadakis, K., Voight, B.F., Scott, L.J., Zhang, F., Farrall, M., Tanaka, T., Wallace, C., Chambers, J.C., Khaw, K.T., Nilsson, P., van der Harst, P., Polidoro, S., Grobbee, D.E., Onland-Moret, N.C., Bots, M.L., Wain, L.V., Elliott, K.S., Teumer, A., Luan, J., Lucas, G., Kuusisto, J., Burton, P.R., Hadley, D., McArdle, W.L., Wellcome Trust Case Control Consortium, X, Brown, M., Dominiczak, A., Newhouse, S.J., Samani, N.J., Webster, J., Zeggini, E., Beckmann, J.S., Bergmann, S., Lim, N., Song, K., Vollenweider, P., Waeber, G., Waterworth, D.M., Yuan, X., Groop, L., Orho, M., Allione, A., Di Gregorio, A., Guarrera, S., Panico, S., Ricceri, F., Romanazzi, V., Sacerdote, C., Vineis, P., Barroso, I., Sandhu, M.S., Luben, R.N., Crawford, G.J., Jousilahti, P., Perola, M., Boehnke, M., Bonnycastle, L.L., Collins, F.S., Jackson, A.U., Mohlke, K.L., Stringham, H.M., Valle, T.T., Willer, C.J., Bergman, R.N., Morken, M.A., Döring, A., Gieger, C., Illig, T., Meitinger, T., Org, E., Pfeufer, A., Wichmann, H.E., Kathiresan, S., Marrugat, J., O'Donnell, C.J., Schwartz, S.M., Siscovick, D.S., Subirana, I., Freimer, N.B., Hartikainen, A.L., McCarthy, M.I., OReilly, P.F., Peltonen, L., Pouta, A., de Jong, P.E., Snieder, H., van Gilst, W.H., Clarke, R., Goel, A., Hamsten, A., Peden, J.F., Seedorf, U., Syv, C., Tognoni, G., Lakatta, E.G., Sanna, S., Scheet, P., Schlessinger, D., Scuteri, A., Dörr, M., Ernst, F., Felix, S.B., Homuth, G., Lorbeer, R., Reffelmann, T., Rettig, R., Völker, U., Galan, P., Gut, I.G., Hercberg, S., Lathrop, G.M., Zeleneka, D., Deloukas, P., Soranzo, N., Williams, F.M., Zhai, G., Salomaa, V., Laakso, M., Elosua, R., Forouhi, N.G., Völzke, H., Uiterwaal, C.S., van der Schouw, Y.T., Numans, M.E., Matullo, G., Navis, G., Berglund, G., Bingham, S.A., Kooner, J.S., Paterson, A.D., Connell, J.M., Bandinelli, S., Ferrucci, L., Watkins, H., Spector, T.D., Tuomilehto, J., Altshuler, D., Strachan, D.P., Laan, M., Meneton, P., Wareham, N.J., Uda, M., Jarvelin, M.R., Mooser, V., Melander, O., Loos, R.J., Elliott, P., Abecasis, G.R., Caulfield, M., Munroe, P.B., Attwood, T., Belz, S., Braund, P., Brocheton, J., Cambien, F., Cooper, J., Crisp-Hihn, A., Diemert, P., Eardman, J., Foad, N., Godefroy, T., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimer, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Liljedahl, U., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Montalescot, G., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Proust, C., Rankin, A., Rendon, A., Rice, C.M., Sager, H.B., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Schunkert, H., Stephens, J., Syvannen, A.C., and Tennstedt, S.
Subjects: Male, Linkage disequilibrium, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, cardiovascular-disease, population, Genome-wide association study, Genetic Loci, Blood Pressure, ANGIOTENSINOGEN, 030204 cardiovascular system & hematology, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Receptors, common variants, Genetics(clinical), ESSENTIAL-HYPERTENSION, Genetics (clinical), POPULATION, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, education.field_of_study, Adult, Aged, Blood Pressure/genetics, Case-Control Studies, Female, Gene Expression Profiling, Genome-Wide Association Study, Haplotypes, Humans, Hypertension/genetics, Middle Aged, Plasma Membrane Calcium-Transporting ATPases/genetics, Polymorphism, Single Nucleotide, Receptors, Atrial Natriuretic Factor/genetics, Sequence Analysis, DNA, COMMON VARIANTS, Single Nucleotide, 3. Good health, SNP genotyping, CARDIOVASCULAR-DISEASE, Hypertension, Sequence Analysis, Atrial Natriuretic Factor, QUANTITATIVE-TRAIT LOCI, metaanalysis, essential-hypertension, SUSCEPTIBILITY LOCI, Population, Single-nucleotide polymorphism, Biology, Article, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, Polymorphism, GENOME-WIDE ASSOCIATION, education, Genotyping, Allele frequency, METAANALYSIS, Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, quantitative-trait loci, Haplotype, Receptors, Atrial Natriuretic Factor, DNA, susceptibility loci, angiotensinogen, Hypertension/*genetics, genome-wide association, linkage disequilibrium
Abstract: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 x 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery, and follow-up data identified SNPs significantly associated with BP at p < 8.56 x 10(-7) at four further loci (NPR3, FIFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. ispartof: American Journal of Human Genetics vol:89 issue:6 pages:688-700 ispartof: location:United States status: published
Published: 2011
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32. Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

Author: Spector, Tim D., Rotimi, Charles N., Hedblad, Bo, Brand, Eva, Day, Ian N. M., Kita, Yoshikuni, Chandak, Giriraj R., Tomaszewski, Maciej, Wong, Andrew, Ogihara, Toshio, Salomaa, Veikko, Igl, Wilmar, Laitinen, Jaana, Olden, Matthias, Okamura, Tomonori, Peltonen, Leena, Witteman, Jacqueline C. M., Wichmann, H-erich, Palmer, Lyle J., Boerwinkle, Eric, Talmud, Philippa J., Tabara, Yasuharu, Platou, Carl G. P., Gyllensten, Ulf B., Meneton, Pierre, Dominiczak, Anna F., Frayling, Timothy M., Groop, Leif, Smith, Albert V., Jackson, Anne U., Kutlar, Abdullah, Heath, Simon, Voight, Benjamin F., Meitinger, Thomas, Stringham, Heather M., Gaunt, Tom R., Islam, Muhammad, Tai, E. Shyong, Hofman, Albert, Lohman, Kurt K., Rotter, Jerome I., Hoffman Bolton, Judith A., Schouw, Yvonne T., Raffel, Leslie J., Lawrence, Robert W., Rudock, Megan E., Scuteri, Angelo, Peden, John F., Eyheramendy, Susana, Aspelund, Thor, Adair, Linda S., Demirkan, Ayse, Staessen, Jan A., Glazer, Nicole L., Launer, Lenore, Ganesh, Santhi, Hirschorn, Joel N., Seshadri, Sudha, Sjo&#776, gren, Marketa, Musani, Solomon K., Verwoert, Germaine C., Umemura, Satoshi, Bis, Joshua C., Dreisbach, Albert W., Keating, Brendan J., Ala-korpela, Mika, Hartikainen, Anna-liisa, Galan, Pilar, Strachan, David P., Hadley, David, Prokopenko, Inga, Young, J. Hunter, Ehret, Georg B., Prabhakaran, Dorairajan, Scott, Laura J., Mosley, Thomas H., Viikari, Jorma, Ohkubo, Takayoshi, Wiggins, Kerri L., Emilsson, Valur, Salako, Tunde, Vo&#776, lker, Uwe, Bornstein, Stefan R., lzke, Henry, Dries, Daniel L., Sharma, Pankaj, Ueshima, Hirotsugu, Wright, Alan F., Lee, Nanette R., Loos, Ruth J. F., Lawlor, Debbie A., Kathiresan, Sekar, Cho, Yoon Shin, Luan, Jian An, Jafar, Tazeen H., Bakker, Stephan J. L., Altshuler, David, Arking, Dan E., Tayo, Bamidele O., Smith, George Davey, Liu, Kiang, Taylor, Herman A., Parsa, Afshin, Mattace-raso, Francesco U. S., Wild, Sarah H., Guo, Xiuqing, Shuldiner, Alan R., Zhang, Weihua, Zhang, Feng, Harris, Tamara B., Kuusisto, Johanna, Zukowska-szczechowska, Ewa, Nyberg, Fredrik, Vineis, Paolo, Dahgam, Santosh, Hayward, Caroline, Hicks, Andrew A., Kuh, Diana, Shriner, Daniel, Taylor, Andrew, Mckenzie, Colin A., Wang, Thomas J., Steinle, Nanette I., Elosua, Roberto, Sim, Xueling, Kang, Sun J., Rivadeneira, Fernando, Palmen, Jutta, Cooper, Matthew N., Lyon, Helen N., Levy, Daniel, Swift, Amy J., Raitakari, Olli, Lyytika&#776, inen, Leo-pekka, Saleheen, Danish, Rudan, Igor, Schwarz, Peter E. H., Kooner, Jaspal S., Smith, Nicholas L., Matullo, Giuseppe, Barroso, Ine&#770, s, O Connell, Jeffrey R., Hunt, Steven C., Hernandez, Dena, Erdmann, Jeanette, Wu&#776, rz, Peter, Forrester, Terrence, Burton, Paul R., Ongen, Halit, Bandinelli, Stefania, Thelle, Dag S., Sehmi, Joban S., O Reilly, Paul F., Braund, Peter S., Danesh, John, Wyatt, Sharon B., Parker, Alex N., Polak, Josef F., Collins, Rory, Zhao, Jing Hua, Shi, Gang, Dehghan, Abbas, Rosengren, Annika, Whincup, Peter H., Duijn, Cornelia M., Hwang, Shih-jen, Ridker, Paul M., Chakravarti, Aravinda, Uda, Manuela, Tanaka, Toshiko, Pramstaller, Peter P., Morken, Mario A., Soininen, Pasi, Abecasis, Gonc&#807, alo R., Zhai, Guangju, Curb, J. David, Ferrucci, Luigi, Doumatey, Ayo P., Fox, Ervin R., Bergman, Richard N., Johnson, Toby, Larson, Martin G., Snieder, Harold, Morris, Richard W., Onland-moret, N. Charlotte, Johnson, Andrew D., Narisu, Narisu, Samani, Nilesh J., Pihur, Vasyl, Chaturvedi, Nish, Melander, Olle, Hamsten, Anders, Charchar, Fadi J., Ludwig, Barbara, Kim, Hyung-lae, Bergmann, Sven, Nalls, Michael A., Milaneschi, Yuri, Palmer, Nicholette D., Alexander, Myriam, Townsend, Raymond R., Caulfield, Mark J., Hilton, Gina, Tuomilehto, Jaakko, Lee, Jong-young, Perola, Markus, Grobbee, Diederick E., Longstreth, Will T., Munroe, Patricia B., Uitterlinden, Andre G., Iwai, Naoharu, Adeyemo, Adebowale, Cooper, Richard S., Mcardle, Wendy L., Sun, Yan V., Sijbrands, Eric J. G., Fabsitz, Richard R., Nguyen, Khanh-dung Hoang, Martin, Lisa W., Wareham, Nicholas J., Brown, Morris J., Wang, Xiaoling, Kuznetsova, Tatiana, Rao, Dabeeru C., Org, Elin, Gilst, Wiek H., Orru, Marco, Oostra, Ben A., Howard, Philip, Wagenknecht, Lynne E., Meschia, James F., Mooser, Vincent, Lehtima&#776, ki, Terho, Wong, Tien Y., Langefeld, Carl D., Bragg-gresham, Jennifer L., Bochud, Murielle, Arora, Pankaj, Kivimaki, Mika, Seielstad, Mark, O Donnell, Chris, Chasman, Daniel I., Farrall, Martin, Polasek, Ozren, Fava, Cristiano, Vitart, Veronique, Mani, K. Radha, Uiterwaal, Cuno S. P. M., Chang, Yen-pei C., Zhu, Haidong, Morrison, Alanna C., Bonnycastle, Lori L., Najjar, Samer, Vollenweider, Peter, Eaton, Charles B., Singleton, Andrew, Teumer, Alexander, Deloukas, Panos, Campbell, Harry, Terzic, Janos, Aulchenko, Yurii, Farlow, Deborah N., Psaty, Bruce M., Beckmann, Jacques S., Scott, James, Tobin, Martin D., Kao, Wen Hong Linda, Harst, Pim, Amin, Najaf, Zitting, Paavo, Pattaro, Cristian, Casas, Juan P., Ikram, M. Arfan, Coresh, Josef, Hingorani, Aroon D., Kulkarni, Smita R., Shrine, Nick R. G., Yao, Jie, Fowkes, F. Gerald R., Clarke, Robert, Gra&#776, ssler, Ju&#776, rgen, Hercberg, Serge, Wain, Louise V., Redline, Susan, Isaacs, Aaron, Hopewell, Jemma C., Lathrop, Mark, Vinay, D. G., Marmot, Michael G., Laan, Maris, Rasheed, Asif, So&#771, ber, Siim, Vartiainen, Erkki, Han, Bok-ghee, Rettig, Rainer, Kinra, Sanjay, Artigas, Maria Soler, Veldre, Gudrun, Navis, Gerjan, Shaw-hawkins, Sue, Franceschini, Nora, Lucas, Gavin, Penman, Alan D., Ong, Rick Twee-hee, Mohlke, Karen L., Beilby, John P., Zhu, Xiaofeng, Bots, Michiel L., Chen, Ming-huei, Denniff, Matthew, Brand, Stefan-martin, Kangas, Antti J., Hveem, Kristian, Chambers, John C., Tukiainen, Taru, Boehnke, Michael, Ramachandran, Vasan S., Connell, John M., Collins, Francis S., Khaw, Kay-tee, Nilsson, Peter, Wilson, James F., Yajnik, Chittaranjan S., Guarrera, Simonetta, Gieger, Christian, Elliott, Paul, Plump, Andrew, Ricceri, Fulvio, Tzoulaki, Ioanna, Garcia, Melissa, Ka&#776, ho&#776, nen, Mika, Laakso, Markku, Kumari, Meena, Stanca&#769, kova&#769, Alena, Corsi, Anna Maria, Soranzo, Nicole, Kettunen, Johannes, Gudnason, Vilmundur, Kardia, Sharon L. R., Hardy, Rebecca, Lakatta, Edward G., Goel, Anuj, Liu, Yongmei, Dong, Yanbin, Humphries, Steve E., Rice, Kenneth M., Newton-cheh, Christopher, Ko&#776, ttgen, Anna, Viigimaa, Margus, Tripathy, Vikal, Mangino, Massimo, Janipalli, Charles S., Heckbert, Susan R., Palmas, Walter, Watkins, Hugh, Do&#776, rr, Marcus, Kroemer, Heyo K., Weder, Alan B., Wu, Ying, Schwartz, Steven M., Miki, Tetsuro, Zelenika, Diana, Cooper, Jackie A., Kumar, M. J. Kranthi, International Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS), Ja&#776, rvelin, Marjo-riitt, EchoGen consortium, CARDIoGRAM consortium, CKDGen consortium, Charge-hf, Consortium, KidneyGen consortium, Medical Research Council (MRC), Kuznetsova, Tatiana, Staessen, Jan A, Pediatrics, Ehret, Georg Benedikt, International Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS), CARDIoGRAM consortium, CKDGen consortium, KidneyGen consortium, EchoGen consortium, CHARGE-HF consortium, Morrison, Alanna C [0000-0001-6381-4296], Ramachandran, Vasan S [0000-0001-7357-5970], Adeyemo, Adebowale [0000-0002-3105-3231], Martin, Lisa W [0000-0003-4352-0914], Caulfield, Mark J [0000-0001-9295-3594], Levy, Daniel [0000-0003-1843-8724], Apollo - University of Cambridge Repository, Epidemiologie, and RS: CARIM School for Cardiovascular Diseases
Subjects: Male, Candidate gene, Blood pressure, GWAS, genetic variant, African Americans, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, Cardiovascular, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, Diastole, 2.1 Biological and endogenous factors, International Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS), European Continental Ancestry Group/genetics, Aetiology, International HapMap Project, International Consortium for Blood Pressure Genome-wide Association Studies, Genetics (clinical), ddc:616, Genetics, Genetics & Heredity, 0303 health sciences, Association Studies Articles, Single Nucleotide, General Medicine, 11 Medical And Health Sciences, Biological Sciences, Middle Aged, 3. Good health, Phenotype, Hypertension, Female, Adult, Genotype, Systole, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, genome-wide association, hypertension prevalence, receptor, disease, family, loci, vasculature, awareness, traits, design, 03 medical and health sciences, Clinical Research, Genetic variation, Humans, Genetic variability, Polymorphism, Hypertension/epidemiology/genetics, Molecular Biology, 030304 developmental biology, Genetic association, Aged, African Americans/genetics, Human Genome, 06 Biological Sciences, Black or African American, Genetic Loci, Genome-Wide Association Study, Hypertension/epidemiology, Hypertension/genetics, Imputation (genetics)
Abstract: The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity. ispartof: HUMAN MOLECULAR GENETICS vol:20 issue:11 pages:2273-2284 ispartof: location:England status: published
Published: 2011
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33. Altered regulation of the epithelial sodium channel in hypertension. From genes to therapeutics

Author: Diez-Martinez, J. (Javier)
Subjects: Epithelial Sodium Channel/genetics, Hypertension/metabolism, Hypertension/genetics
Published: 2011

34. Eight blood pressure loci identified by a genome-wide association study of 34'433 people of European ancestry

Author: Caulfield Mark, J., Bochud, Murielle, and Global BPGen Consortium
Subjects: Hypertension/genetics, Cardiovascular Diseases/prevention & control, European Continental Ancestry Group
Published: 2009

35. Arterial properties in relation to genetic variations in the adducin subunits in a white population

Author: Yu Jin, Robert Fagard, Jan A. Staessen, Giuseppe Bianchi, Harry A.J. Struijker-Boudier, Murielle Bochud, Nunzia Casamassima, Paulo Manunta, Tom Richart, Tatiana Kuznetsova, Lorena Citterio, Tim S. Nawrot, Jitka Seidlerová, Jan Filipovský, Seidlerova, J, Staessen, Ja, Bochud, M, Nawrot, T, Casamassima, N, Citterio, L, Kuznetsova, T, Jin, Y, Manunta, Paolo, Richart, T, STRUIJKER BOUDIER, Ha, Fagard, R, Filipovsky, J, and Bianchi, G.
Subjects: Male, Pathology, Brachial Artery, 030204 cardiovascular system & hematology, Polymerase Chain Reaction, 0302 clinical medicine, Belgium, Polymorphism (computer science), Brachial artery, Child, Ultrasonography, Aged, 80 and over, 0303 health sciences, education.field_of_study, Middle Aged, 3. Good health, Femoral Artery, Carotid Arteries, Hypertension, Female, Adult, medicine.medical_specialty, Adolescent, Offspring, Population, Alpha (ethology), Population stratification, White People, Aged, Belgium/epidemiology, Brachial Artery/physiopathology, Brachial Artery/ultrasonography, Calmodulin-Binding Proteins/genetics, Carotid Arteries/physiopathology, Carotid Arteries/ultrasonography, Cytoskeletal Proteins, DNA/genetics, European Continental Ancestry Group, Femoral Artery/physiopathology, Femoral Artery/ultrasonography, Genetic Variation, Humans, Hypertension/ethnology, Hypertension/genetics, Retrospective Studies, Vascular Resistance/genetics, Young Adult, 03 medical and health sciences, Internal medicine, medicine.artery, Internal Medicine, medicine, Allele, education, 030304 developmental biology, business.industry, DNA, Heritability, Endocrinology, Calmodulin-Binding Proteins, Vascular Resistance, business
Abstract: BACKGROUND: Adducin is a membrane skeleton protein, which consists of either alpha- and beta- or alpha- and gamma-subunits. We investigated whether arterial characteristics might be related to the genes encoding ADD1 (Gly460Trp-rs4961), ADD2 (C1797T-rs4984), and ADD3 (IVS11+386A>G-rs3731566). METHODS: We randomly recruited 1,126 Flemish subjects (mean age, 43.8 years; 50.3% women). Using a wall-tracking ultrasound system, we measured the properties of the carotid, femoral, and brachial arteries. We studied multivariate-adjusted phenotype-genotype associations, using a population- and family-based approach. RESULTS: In single-gene analyses, brachial diameter was 0.15 mm (P = 0.0022) larger, and brachial distensibility and cross-sectional compliance were 1.55 x 10(-3)/kPa (P = 0.013) and 0.017 mm(2)/kPa (P = 0.0029) lower in ADD3 AA than ADD3 GG homozygotes with an additive effect of the G allele. In multiple-gene analyses, the association of brachial diameter and distensibility with the ADD3 G allele occurred only in ADD1 GlyGly homozygotes. Otherwise, the associations between the arterial phenotypes in the three vascular beds and the ADD1 or ADD2 polymorphisms were not significant. In family-based analyses, the multivariate-adjusted heritability was 0.52, 0.38, and 0.30 for brachial diameter, distensibility, and cross-sectional compliance, respectively (P < 0.001). There was no evidence for population stratification (0.07 < or = P < or = 0.96). Transmission of the mutated ADD3 G allele was associated with smaller brachial diameter in 342 informative offspring (-0.12 +/- 0.04 mm; P = 0.0085) and in 209 offspring, who were ADD1 GlyGly homozygotes (-0.14 +/- 0.06 mm; P = 0.018). CONCLUSIONS: In ADD1 GlyGly homozygotes, the properties of the brachial artery are related to the ADD3 (A386G) polymorphism, but the underlying mechanism needs further clarification. ispartof: American Journal of Hypertension vol:22 issue:1 pages:21-26 ispartof: location:United States status: published
Published: 2009

36. Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension

Author: Jobs, Alexander, Schmidt, Kjestine, Schmidt, Volker J, Lübkemeier, Indra, van Veen, Toon A B, Kurtz, Armin, Willecke, Klaus, de Wit, Cor, Jobs, Alexander, Schmidt, Kjestine, Schmidt, Volker J, Lübkemeier, Indra, van Veen, Toon A B, Kurtz, Armin, Willecke, Klaus, and de Wit, Cor
Abstract: The gap junction channel protein connexin40 (Cx40) is crucial in vascular and renal physiology, because Cx40-deficient mice exhibit impaired conduction of endothelium-dependent dilations and pronounced hypertension. The latter precludes mechanistic insights into the role of endothelial Cx40, because long-lasting hypertension itself may affect conduction and Cx expression. We aimed to identify endothelial Cx40 functions, their dependency on the conductive capability, and to separate these from hypertension-related alterations. We assessed conduction and Cx expression in mice with cell type-specific deletion of Cx40 and in mice expressing a defective Cx40 (Cx40A96S) identified in humans, which forms nonconducting gap junction channels. Confined arteriolar stimulation with acetylcholine or bradykinin elicited local dilations that conducted upstream without attenuation of the amplitude for distances up to 1.2-mm in controls with a floxed Cx40 gene (Cx40(fl/fl)). Conducted responses in hypertensive animals devoid of Cx40 in renin-producing cells were unaltered but remote dilations were reduced in normotensive animals deficient for Cx40 in endothelial cells (Cx40(fl/fl):Tie2-Cre). Surprisingly, Cx37 expression was undetectable by immunostaining in arteriolar endothelium only in Cx40(fl/fl):Tie2-Cre; however, transcriptional activity of Cx37 in the cremaster was comparable with Cx40(fl/fl) controls. Cx40A96S mice were hypertensive with preserved expression of Cx40 and Cx37. Nevertheless, conducted responses were blunted. We conclude that endothelial Cx40 is necessary to support conducted dilations initiated by endothelial agonists and to locate Cx37 into the plasma membrane. These functions are unaltered by long-lasting hypertension. In the presence of a nonconducting Cx40, Cx37 is present but cannot support the conduction highlighting the importance of endothelial Cx40.
Published: 2012

37. Human microRNA-155 on Chromosome 21 Differentially Interacts with Its Polymorphic Target in the AGTR1 3′ Untranslated Region: A Mechanism for Functional Single-Nucleotide Polymorphisms Related to Phenotypes

Author: Stylianos E. Antonarakis, Samuel Deutsch, Christelle Borel, Praveen Sethupathy, Artemis G. Hatzigeorgiou, Gregory R. Grant, Terry S. Elton, and Maryline Gagnebin
Subjects: Untranslated region, Chromosomes, Human, Pair 21, Molecular Sequence Data, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Receptor, Angiotensin, Type 1, 03 medical and health sciences, 0302 clinical medicine, Report, Genetics, medicine, Gene silencing, Humans, Genetics(clinical), Allele, Gene, 3' Untranslated Regions, Genetics (clinical), Down Syndrome/genetics, 030304 developmental biology, ddc:616, 0303 health sciences, Base Sequence, Three prime untranslated region, Receptor, Angiotensin, Type 1/ genetics, Reproducibility of Results, MicroRNAs/ genetics, medicine.disease, Molecular biology, MicroRNAs, Phenotype, Hypertension, Down Syndrome, Trisomy, Chromosome 21, Hypertension/genetics
Abstract: Animal microRNAs (miRNAs) regulate gene expression through base pairing to their targets within the 3' untranslated region (UTR) of protein-coding genes. Single-nucleotide polymorphisms (SNPs) located within such target sites can affect miRNA regulation. We mapped annotated SNPs onto a collection of experimentally supported human miRNA targets. Of the 143 experimentally supported human target sites, 9 contain 12 SNPs. We further experimentally investigated one of these target sites for hsa-miR-155, within the 3' UTR of the human AGTR1 gene that contains SNP rs5186. Using reporter silencing assays, we show that hsa-miR-155 down-regulates the expression of only the 1166A, and not the 1166C, allele of rs5186. Remarkably, the 1166C allele has been associated with hypertension in many studies. Thus, the 1166C allele may be functionally associated with hypertension by abrogating regulation by hsa-miR-155, thereby elevating AGTR1 levels. Since hsa-miR-155 is on chromosome 21, we hypothesize that the observed lower blood pressure in trisomy 21 is partially caused by the overexpression of hsa-miR-155 leading to allele-specific underexpression of AGTR1. Indeed, we have shown in fibroblasts from monozygotic twins discordant for trisomy 21 that levels of AGTR1 protein are lower in trisomy 21.
Published: 2007

38. Renal determinants of the salt sensitivity of blood pressure

Author: Chiolero, A., Würzner, G., and Burnier, M.
Subjects: Blood Pressure/drug effects, Hemodynamics/drug effects, Hormones/metabolism, Humans, Hypertension/chemically induced, Hypertension/genetics, Kidney/physiology, Renal Circulation/drug effects, Risk Factors, Sodium Chloride/pharmacology
Published: 2001

39. Angiotensinogen gene promoter haplotype and microangiopathy-related cerebral damage: results of the Austrian Stroke Prevention Study

Author: Schmidt, H. (Helena), Fazekas, F. (Franz), Kostner, G.M., Schmidt, R. (Reinhold), Duijn, C.M. (Cornelia) van, Schmidt, H. (Helena), Fazekas, F. (Franz), Kostner, G.M., Schmidt, R. (Reinhold), and Duijn, C.M. (Cornelia) van
Abstract: BACKGROUND AND PURPOSE: Microangiopathy-related cerebral damage (MARCD) is a common finding in the elderly. It may lead to cognitive impairment and gait disturbances. Arterial hypertension and age are the most important risk factors. We assessed the association between MARCD and sequence alterations in the promoter region of the angiotensinogen (AGT) gene. METHODS: We studied 410 randomly selected community-dwelling individuals aged 50 to 75 years. MARCD was defined as early confluent or confluent white matter hyperintensities or lacunes on a 1.5-T MRI. The AGT promoter was analyzed by temporal temperature gradient gel electrophoresis and automated sequencing. RESULTS: We detected 4 polymorphic sites, at positions -6, -20, -153, and -218. They created 5 haplotypes, which we coded as A (-6:g, -20:a, -153:g, -218g), B (-6:a, -20:c, -153:g, -218:g), C (-6:a, -20:c, -153:a, -218:g), D (-6:a, -20:a, -153:g, -218:g), and E (-6:a, -20:a, -153:g, -218:a). MARCD was seen in 7 subjects (63.6%) carrying 2 copies of the B haplotype (B/B), in 12 subjects (38.7%) carrying 1 copy of the B haplotype in the absence of the A haplotype (B+/A-), but in only 70 subjects (19.0%) in the remaining cohort (P:<0.001). The odds ratios for the B/B and the B+/A- genotypes were 8.0 (95% CI, 2.1 to 31.1; P:=0.003) and 1.8 (95% CI, 0.8 to 4.2; P:=0.14) after adjustment for possible confounders. CONCLUSIONS: The B haplotype of the AGT promoter in the absence of the wild-type A haplotype might represent a genetic susceptibility factor for MARCD.
Published: 2001

40. A genetic deficiency in calpastatin and isovalerylcarnitine treatment is associated with enhanced hippocampal long-term potentiation

Author: Isabella Molinari, Giuseppe Bianchi, Laura Soldati, and Dominique Muller
Subjects: medicine.medical_specialty, Long-Term Potentiation, Hippocampus, Endogeny, Carnitine/ analogs & derivatives/deficiency, Hippocampal formation, Cellular and Molecular Neuroscience, Inbred strain, Internal medicine, Carnitine, Rats, Inbred SHR, medicine, Animals, Rats, Wistar, Calpastatin, Hippocampus/ drug effects, biology, Chemistry, Calpain, Calcium-Binding Proteins, Long-term potentiation, Rats, Inbred Strains, Calpain/antagonists & inhibitors, ddc:616.8, Rats, Endocrinology, Calcium-Binding Proteins/ deficiency, Hypertension, biology.protein, NMDA receptor, Neuroscience, Hypertension/genetics
Abstract: The Milan hypertensive strain (MHS) of rats, in addition to having hypertension, is also characterized by a genetic deficiency in calpastatin, the endogenous inhibitor of calpain. Since this protease has been implicated in long-term potentiation (LTP), we have investigated whether induction of this form of plasticity was altered in this strain of rats as compared to control animals (Milan normotensive strain, MNS). Progressive induction of LTP by increasing numbers of high frequency trains resulted in a greater degree of potentiation measured with all inducing protocols in MHS as compared with MNS animals. This difference was not related to the hypertension, since another hypertensive strain (the SHR strain) and a segregated Milan hypertensive strain, expressing only the hypertension but not the calpastatin deficiency (the MHNE strain), exhibited an LTP indistinguishable from control rats. Treatment of MHNE rats for 2 months with isovalerylcarnitine, a compound that increases calpain activity, also resulted in a greater amount of LTP induced by high frequency trains. These effects were not related to an enhancement of the NMDA receptor dependent component of responses to burst stimulation. These results are consistent with the idea that conditions under which calpain activation is facilitated are associated with a greater degree of synaptic potentiation.
Published: 1995

41. Estrogen effects in the heart.

Author: Pelzer, T., Shamim, A., Neyses, Ludwig, Pelzer, T., Shamim, A., and Neyses, Ludwig
Abstract: Gender specific differences in cardiovascular disease are largely mediated by sex hormones. The use of estrogens significantly reduces the overall incidence of heart disease in postmenopausal women. Beneficial effects of estrogens on plasma lipoprotein levels are clearly established. However, these do not explain the magnitude of risk reduction seen in clinical studies. Thus additional and currently unknown functions of estrogens must be operative. Elucidation of the exact estrogen action in the heart will have important implications in the treatment of cardiovascular disease. It will probably enhance the therapeutic repertoire in treating heart disease, the most common cause of death in industrialized countries. We will review the current understanding of the function of estrogens in the heart and discuss potential strategies on how to apply these data to clinical practice.
Published: 1996

42. SNPs and Other Features as They Predispose to Complex Disease: Genome-Wide Predictive Analysis of a Quantitative Phenotype for Hypertension

Author: Richard A. Olshen, Georg Ehret, Joong-Ho Won, and Aravinda Chakravarti
Subjects: False discovery rate, Epidemiology, lcsh:Medicine, Genome-wide association study, Cardiovascular, 01 natural sciences, 010104 statistics & probability, lcsh:Science, Epidemiological Methods, ddc:616, Genetics, 0303 health sciences, Multidisciplinary, Statistics, Genomics, Middle Aged, Polymorphism, Single Nucleotide/genetics, Regression, 3. Good health, Phenotype, Nephrology, Genetic Epidemiology, Hypertension, Genome-Wide Association Study/methods, Medicine, Female, Algorithms, Research Article, Single-nucleotide polymorphism, Biostatistics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genome Analysis Tools, Linear regression, Genome-Wide Association Studies, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Statistical Methods, 0101 mathematics, Genetic Association Studies, Aged, 030304 developmental biology, Genetic association, Evolutionary Biology, Population Biology, lcsh:R, Computational Biology, Human Genetics, Genetic Polymorphism, lcsh:Q, Hypertension/genetics, Population Genetics, Mathematics, Genome-Wide Association Study
Abstract: Though recently they have fallen into some disrepute, genome-wide association studies (GWAS) have been formulated and applied to understanding essential hypertension. The principal goal here is to use data gathered in a GWAS to gauge the extent to which SNPs and their interactions with other features can be combined to predict mean arterial blood pressure (MAP) in 3138 pre-menopausal and naturally post-menopausal white women. More precisely, we quantify the extent to which data as described permit prediction of MAP beyond what is possible from traditional risk factors such as blood cholesterol levels and glucose levels. Of course, these traditional risk factors are genetic, though typically not explicitly so. In all, there were 44 such risk factors/clinical variables measured and 377,790 single nucleotide polymorphisms (SNPs) genotyped. Data for women we studied are from first visit measurements taken as part of the Atherosclerotic Risk in Communities (ARIC) study. We begin by assessing non-SNP features in their abilities to predict MAP, employing a novel regression technique with two stages, first the discovery of main effects and next discovery of their interactions. The long list of SNPs genotyped is reduced to a manageable list for combining with non-SNP features in prediction. We adapted Efron's local false discovery rate to produce this reduced list. Selected non-SNP and SNP features and their interactions are used to predict MAP using adaptive linear regression. We quantify quality of prediction by an estimated coefficient of determination (R(2)). We compare the accuracy of prediction with and without information from SNPs.
Published: 2011
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43. The biological cascade leading to cardiac hypertrophy.

Author: Neyses, Ludwig, Pelzer, T., Neyses, Ludwig, and Pelzer, T.
Abstract: Cardiac hypertrophy, one of the major risk factors in hypertension, is associated with a high incidence of congestive heart failure and sudden death. Despite efforts over the last 20 years, the underlying molecular mechanisms of cardiac hypertrophy are still poorly understood, thus making it difficult to develop new therapeutic strategies. A growing body of evidence suggests that cardiac hypertrophy results from mechanical stress that triggers paracrine and autocrine signal transduction pathways. Furthermore, whereas hypertrophy leads to isoform switches in some contractile proteins, increased protein synthesis is largely based on increased translational capacity. Cardiac growth under physiological as well as pathological conditions is regulated by several recently identified transcription factors. Among the factors that are capable of transmitting hypertrophic stimuli to the nucleus is the early growth response gene-1 (Egr-1). Whereas female gender is already an established cardioprotective factor in clinical trials, some very recent data indicate that oestrogens and the nuclear oestrogen receptor may directly modulate gene expression in the development of cardiac hypertrophy. Future pharmacological interventions could be directed towards modifying the nuclear signal transduction cascade involving multiple protein kinases and phosphatases.
Published: 1995

44. Essential hypertension and inheritance of vascular reactivity.

Author: DOYLE AE and FRASER JR
Subjects: Essential Hypertension, Humans, Blood Vessels abnormalities, Heredity, Hypertension genetics
Published: 1961
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45. The family of hypertensive man.

Author: PERERA GA, CLARK EG, GEARING FR, and SCHWEITZER MD
Subjects: Humans, Male, Hypertension genetics
Published: 1960

46. Circulatory reactions of normotensive and hypertensive subjects and of the children of normal and hypertensive parents.

Author: REMINGTON RD, LAMBARTH B, MOSER M, and HOOBLER SW
Subjects: Child, Humans, Blood Pressure, Blood Pressure Determination, Cardiovascular Abnormalities, Hypertension genetics, Parents
Published: 1960
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