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12 results on '"Hypertension/genetics"'

1. 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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2. 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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3. 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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4. 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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5. 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. 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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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6. 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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7. 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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8. 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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9. 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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10. 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

11. 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

12. 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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