Search

Your search keyword '"Smelser, Diane T"' showing total 49 results
Start Over Author "Smelser, Diane T"

Refine your results

more »

more »

more »

more »
49 results on '"Smelser, Diane T"'

1. Genome-first approach of the prevalence and cancer phenotypes of pathogenic or likely pathogenic germline TP53 variants

Author

de Andrade, Kelvin C., Strande, Natasha T., Kim, Jung, Haley, Jeremy S., Hatton, Jessica N., Frone, Megan N., Khincha, Payal P., Thone, Gretchen M., Mirshahi, Uyenlinh L., Schneider, Cynthia, Desai, Heena, Dove, James T., Smelser, Diane T., Levine, Arnold J., Maxwell, Kara N., Stewart, Douglas R., Carey, David J., and Savage, Sharon A.

Published
2024
Full Text
View/download PDF

2. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

4. Genetic risk models: Influence of model size on risk estimates and precision

Author

Shan, Ying, Tromp, Gerard, Kuivaniemi, Helena, Smelser, Diane T, Verma, Shefali S, Ritchie, Marylyn D, Elmore, James R, Carey, David J, Conley, Yvette P, Gorin, Michael B, and Weeks, Daniel E

Subjects
Epidemiology, Biological Sciences, Health Sciences, Prevention, Genetics, Aged, Aortic Aneurysm, Abdominal, Computer Simulation, Confidence Intervals, Databases, Genetic, Female, Genetic Predisposition to Disease, Humans, Macular Degeneration, Male, Middle Aged, Models, Genetic, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, Sample Size, disease risk estimation, confidence interval, model size, reclassification, Public Health and Health Services
Abstract

Disease risk estimation plays an important role in disease prevention. Many studies have found that the ability to predict risk improves as the number of risk single-nucleotide polymorphisms (SNPs) in the risk model increases. However, the width of the confidence interval of the risk estimate is often not considered in the evaluation of the risk model. Here, we explore how the risk and the confidence interval width change as more SNPs are added to the model in the order of decreasing effect size, using both simulated data and real data from studies of abdominal aortic aneurysms and age-related macular degeneration. Our results show that confidence interval width is positively correlated with model size and the majority of the bigger models have wider confidence interval widths than smaller models. Once the model size is bigger than a certain level, the risk does not shift markedly, as 100% of the risk estimates of the one-SNP-bigger models lie inside the confidence interval of the one-SNP-smaller models. We also created a confidence interval-augmented reclassification table. It shows that both more effective SNPs with larger odds ratios and less effective SNPs with smaller odds ratios contribute to the correct decision of whom to screen. The best screening strategy is selected and evaluated by the net benefit quantity and the reclassification rate. We suggest that individuals whose upper bound of their risk confidence interval is above the screening threshold, which corresponds to the population prevalence of the disease, should be screened.

Published
2017

6. Genome-First Approach of the Prevalence and Cancer Phenotypes of Pathogenic or Likely Pathogenic Germline TP53 Variants

Author

de Andrade, Kelvin C., primary, Strande, Natasha T., additional, Kim, Jung, additional, Haley, Jeremy S., additional, Hatton, Jessica N., additional, Frone, Megan N., additional, Khincha, Payal P., additional, Thone, Gretchen M., additional, Mirshahi, Uyenlinh L., additional, Schneider, Cynthia, additional, Desai, Heena, additional, Dove, James T., additional, Smelser, Diane T., additional, BioBank, Penn Medicine, additional, Center, Regeneron Genetics, additional, Levine, Arnold J., additional, Maxwell, Kara N., additional, Stewart, Douglas R., additional, Carey, David J., additional, and Savage, Sharon A., additional

Published
2023
Full Text
View/download PDF

8. Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants

Author

Haggerty, Christopher M., Damrauer, Scott M., Levin, Michael G., Birtwell, David, Carey, David J., Golden, Alicia M., Hartzel, Dustin N., Hu, Yirui, Judy, Renae, Kelly, Melissa A., Kember, Rachel L., Lester Kirchner, H., Leader, Joseph B., Liang, Lusha, McDermott-Roe, Chris, Babu, Apoorva, Morley, Michael, Nealy, Zachariah, Person, Thomas N., Pulenthiran, Arichanah, Small, Aeron, Smelser, Diane T., Stahl, Richard C., Sturm, Amy C., Williams, Heather, Baras, Aris, Margulies, Kenneth B., Cappola, Thomas P., Dewey, Frederick E., Verma, Anurag, Zhang, Xinyuan, Correa, Adolfo, Hall, Michael E., Wilson, James G., Ritchie, Marylyn D., Rader, Daniel J., Murray, Michael F., Fornwalt, Brandon K., and Arany, Zoltan

Published
2019
Full Text
View/download PDF

10. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Author

Jones, Gregory T., Tromp, Gerard, Kuivaniemi, Helena, Gretarsdottir, Solveig, Baas, Annette F., Giusti, Betti, Strauss, Ewa, van‘t Hof, Femke N.G., Webb, Thomas R., Erdman, Robert, Ritchie, Marylyn D., Elmore, James R., Verma, Anurag, Pendergrass, Sarah, Kullo, Iftikhar J., Ye, Zi, Peissig, Peggy L., Gottesman, Omri, Verma, Shefali S., Malinowski, Jennifer, Rasmussen-Torvik, Laura J., Borthwick, Kenneth M., Smelser, Diane T., Crosslin, David R., de Andrade, Mariza, Ryer, Evan J., McCarty, Catherine A., Böttinger, Erwin P., Pacheco, Jennifer A., Crawford, Dana C., Carrell, David S., Gerhard, Glenn S., Franklin, David P., Carey, David J., Phillips, Victoria L., Williams, Michael J.A., Wei, Wenhua, Blair, Ross, Hill, Andrew A., Vasudevan, Thodor M., Lewis, David R., Thomson, Ian A., Krysa, Jo, Hill, Geraldine B., Roake, Justin, Merriman, Tony R., Oszkinis, Grzegorz, Galora, Silvia, Saracini, Claudia, Abbate, Rosanna, Pulli, Raffaele, Pratesi, Carlo, Saratzis, Athanasios, Verissimo, Ana R., Bumpstead, Suzannah, Badger, Stephen A., Clough, Rachel E., Cockerill, Gillian, Hafez, Hany, Scott, D. Julian A., Futers, T. Simon, Romaine, Simon P.R., Bridge, Katherine, Griffin, Kathryn J., Bailey, Marc A., Smith, Alberto, Thompson, Matthew M., van Bockxmeer, Frank M., Matthiasson, Stefan E., Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Blankensteijn, Jan D., Teijink, Joep A.W., Wijmenga, Cisca, de Graaf, Jacqueline, Kiemeney, Lambertus A., Lindholt, Jes S., Hughes, Anne, Bradley, Declan T., Stirrups, Kathleen, Golledge, Jonathan, Norman, Paul E., Powell, Janet T., Humphries, Steve E., Hamby, Stephen E., Goodall, Alison H., Nelson, Christopher P., Sakalihasan, Natzi, Courtois, Audrey, Ferrell, Robert E., Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Eicher, John D., Johnson, Andrew D., Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Schadt, Eric E., Björkegren, Johan L.M., Lipovich, Leonard, Drolet, Anne M., Verhoeven, Eric L., Zeebregts, Clark J., Geelkerken, Robert H., van Sambeek, Marc R., van Sterkenburg, Steven M., de Vries, Jean-Paul, Stefansson, Kari, Thompson, John R., de Bakker, Paul I.W., Deloukas, Panos, Sayers, Robert D., Harrison, Seamus C., van Rij, Andre M., Samani, Nilesh J., and Bown, Matthew J.

Published
2017
Full Text
View/download PDF

12. Do Hernias Contribute to Increased Severity of Aneurysmal Disease among Abdominal Aortic Aneurysm Patients?

Author

Hinterseher, Irene, Miszczuk, Milena, Corvinus, Florian, Zimmermann, Carolin, Estrelinha, Mariana, Smelser, Diane T., and Kuivaniemi, Helena

Subjects
abdominal aortic aneurysm, connective tissue disorder, cardiovascular system, macromolecular substances, cardiovascular diseases, Original Research Article, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, hernia
Abstract

Background Connective tissue disorders could contribute to the pathogenesis of both abdominal aortic aneurysms (AAA) and hernias. We tested the hypothesis that hernias in AAA patients contribute to increased severity of the aneurysmal disease. Methods A questionnaire was used to collect information from 195 AAA patients divided into four groups: (1) survivors ( n = 22) of ruptured AAA, (2) patients ( n = 90) after elective open repair, (3) patients ( n = 43) after elective endovascular repair (EVAR), and (4) patients ( n = 40) under surveillance of AAA. The control group consisted of 100 patients without AAA whose abdominal computed tomography (CT) scans were examined for the presence of hernias. Mann–Whitney U -test, Chi-squared ( χ 2 ) test, or Fisher's exact test (as appropriate) were used for statistical analyses. Multivariate logistic regression was used to control for potential confounding variables such as sex and age. Results The prevalence of inguinal hernias was significantly higher in the AAA than the control group (25 vs. 9%, p = 0.001) and did not differ between the AAA subgroups (9, 24, 35, and 23% in subgroups 1 through 4, respectively, p = 0.15) based on univariate analysis. The prevalence of inguinal hernias did not differ ( p = 0.15) between the two open surgery groups (groups 1 and 2), or when comparing all three operative procedures as a combined group to group 4 ( p = 0.73). The prevalences of incisional hernias were 18 and 24% for groups 1 and 2, respectively, with no significant difference ( p = 0.39). Inguinal hernia demonstrated a significant association with AAA on multivariate analysis ( p = 0.006; odds ratio [OR] = 4.00; 95% confidence interval [CI] = 1.49–10.66). Conclusions Our study confirms previous observations that patients with AAA have a high prevalence of hernias. Our results suggest that hernias do not contribute to increased severity of the aneurysmal disease.

Published
2021

13. Familial hypocalciuric hypercalcemia type 1 and autosomal-dominant hypocalcemia type 1: prevalence in a large healthcare population

Author

Dershem, Ridge, Gorvin, Caroline M, Metpally, Raghu PR, Krishnamurthy, Sarathbabu, Smelser, Diane T, Hannan, Fadil M, Carey, David J, Thakker, Rajesh V, Breitwieser, Gerda E, and Ctr, Regeneron Genetics

Subjects
0301 basic medicine, Male, Disease, Cohort Studies, 0302 clinical medicine, Sequence Kernel Association Test, Prevalence, Missense mutation, Genetics (clinical), Genes, Dominant, Genetics, Aged, 80 and over, education.field_of_study, Middle Aged, Phenotype, disease associations, familial hypocalciuric hypercalcemia type 1, Female, Calcium-sensing receptor, Adult, Heterozygote, Population, 030209 endocrinology & metabolism, Article, Frameshift mutation, 03 medical and health sciences, disease prevalence, medicine, genomics, Humans, education, Aged, Familial hypocalciuric hypercalcemia, business.industry, serum calcium, medicine.disease, SKAT, United States, calcium sensing receptor, 030104 developmental biology, Hypoparathyroidism, autosomal-dominant hypocalcemia type 1, Mutation, Hypercalcemia, Calcium, business, Delivery of Health Care, Receptors, Calcium-Sensing, Primary hyperparathyroidism
Abstract

The calcium-sensing receptor (CaSR) regulates serum calcium concentrations. CASR loss- or gain-of-function mutations cause familial hypocalciuric hypercalcemia type 1 (FHH1) or autosomal-dominant hypocalcemia type 1 (ADH1), respectively, but the population prevalence of FHH1 or ADH1 is unknown. Rare CASR variants were identified in whole-exome sequences from 51,289 de-identified individuals in the DiscovEHR cohort derived from a single US healthcare system. We integrated bioinformatics pathogenicity triage, mean serum Ca concentrations, and mode of inheritance to identify potential FHH1 or ADH1 variants, and we used a Sequence Kernel Association Test (SKAT) to identify rare variant-associated diseases. We identified predicted heterozygous loss-of-function CASR variants (6 different nonsense/frameshift variants and 12 different missense variants) in 38 unrelated individuals, 21 of whom were hypercalcemic. Missense CASR variants were identified in two unrelated hypocalcemic individuals. Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling, whereas hypocalcemia-associated missense variants increased expression, plasma membrane targeting, and/or signaling. Thus, 38 individuals with a genetic diagnosis of FHH1 and two individuals with a genetic diagnosis of ADH1 were identified in the 51,289 cohort, giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1. SKAT combining all nonsense, frameshift, and missense loss-of-function variants revealed associations with cardiovascular, neurological, and other diseases. In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism, and is associated with altered disease risks, whereas ADH1 is a major cause of non-surgical hypoparathyroidism.

Published
2020

17. Prevalence and Electronic Health Record-Based Phenotype of Loss-of-Function Genetic Variants in Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes

Author

Carruth, Eric D., primary, Young, Wilson, additional, Beer, Dominik, additional, James, Cynthia A., additional, Calkins, Hugh, additional, Jing, Linyuan, additional, Raghunath, Sushravya, additional, Hartzel, Dustin N., additional, Leader, Joseph B., additional, Kirchner, H. Lester, additional, Smelser, Diane T., additional, Carey, David J., additional, Kelly, Melissa A., additional, Sturm, Amy C., additional, Alsaid, Amro, additional, Fornwalt, Brandon K., additional, and Haggerty, Christopher M., additional

Published
2019
Full Text
View/download PDF

18. Inflammation gene variants and susceptibility to albuminuria in the U.S. population: analysis in the Third National Health and Nutrition Examination Survey (NHANES III), 1991-1994

Author

Chang Man-huei, Moonesinghe Ramal, Smelser Diane T, Imperatore Giuseppina, Yesupriya Ajay, Ned Renée M, and Dowling Nicole F

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria. Methods We evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ≥ 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models. Results Variants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, IL1B (rs1143623) among Mexican Americans remained significantly associated with increased odds, while IL1B (rs1143623), CRP (rs1800947) and NOS3 (rs2070744) were significantly associated with ACR ≥ 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was TNF rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within MBL2, CRP, ADRB2, IL4R, NOS3, and VDR were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group. Conclusions Our findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.

Published
2010
Full Text
View/download PDF

20. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Author

Jones, Gregory T, Tromp, Gerard, Kuivaniemi, Helena, Gretarsdottir, Solveig, Baas, Annette F, Giusti, Betti, Strauss, Ewa, Van't Hof, Femke N G, Webb, Thomas R, Erdman, Robert, Ritchie, Marylyn D, Elmore, James R, Verma, Anurag, Pendergrass, Sarah, Kullo, Iftikhar J, Ye, Zi, Peissig, Peggy L, Gottesman, Omri, Verma, Shefali S, Malinowski, Jennifer, Rasmussen-Torvik, Laura J, Borthwick, Kenneth M, Smelser, Diane T, Crosslin, David R, de Andrade, Mariza, Ryer, Evan J, McCarty, Catherine A, Böttinger, Erwin P, Pacheco, Jennifer A, Crawford, Dana C, Carrell, David S, Gerhard, Glenn S, Franklin, David P, Carey, David J, Phillips, Victoria L, Williams, Michael J A, Wei, Wenhua, Blair, Ross, Hill, Andrew A, Vasudevan, Thodor M, Lewis, David R, Thomson, Ian A, Krysa, Jo, Hill, Geraldine B, Roake, Justin, Merriman, Tony R, Oszkinis, Grzegorz, Galora, Silvia, Saracini, Claudia, Abbate, Rosanna, Pulli, Raffaele, Pratesi, Carlo, Saratzis, Athanasios, Verissimo, Ana R, Bumpstead, Suzannah, Badger, Stephen A, Clough, Rachel E, Cockerill, Gillian, Hafez, Hany, Scott, D Julian A, Futers, T Simon, Romaine, Simon P R, Bridge, Katherine, Griffin, Kathryn J, Bailey, Marc A, Smith, Alberto, Thompson, Matthew M, van Bockxmeer, Frank M, Matthiasson, Stefan E, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Blankensteijn, Jan D, Teijink, Joep A W, Wijmenga, Cisca, de Graaf, Jacqueline, Kiemeney, Lambertus A, Lindholt, Jes S, Hughes, Anne, Bradley, Declan T, Stirrups, Kathleen, Golledge, Jonathan, Norman, Paul E, Powell, Janet T, Humphries, Steve E, Hamby, Stephen E, Goodall, Alison H, Nelson, Christopher P, Sakalihasan, Natzi, Courtois, Audrey, Ferrell, Robert E, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Eicher, John D, Johnson, Andrew D, Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Schadt, Eric E, Björkegren, Johan L M, Lipovich, Leonard, Drolet, Anne M, Verhoeven, Eric L, Zeebregts, Clark J, Geelkerken, Robert H, van Sambeek, Marc R, van Sterkenburg, Steven M, de Vries, Jean-Paul, Stefansson, Kari, Thompson, John R, de Bakker, Paul I W, Deloukas, Panos, Sayers, Robert D, Harrison, Seamus C, van Rij, Andre M, Samani, Nilesh J, Bown, Matthew J, Jones, Gregory T, Tromp, Gerard, Kuivaniemi, Helena, Gretarsdottir, Solveig, Baas, Annette F, Giusti, Betti, Strauss, Ewa, Van't Hof, Femke N G, Webb, Thomas R, Erdman, Robert, Ritchie, Marylyn D, Elmore, James R, Verma, Anurag, Pendergrass, Sarah, Kullo, Iftikhar J, Ye, Zi, Peissig, Peggy L, Gottesman, Omri, Verma, Shefali S, Malinowski, Jennifer, Rasmussen-Torvik, Laura J, Borthwick, Kenneth M, Smelser, Diane T, Crosslin, David R, de Andrade, Mariza, Ryer, Evan J, McCarty, Catherine A, Böttinger, Erwin P, Pacheco, Jennifer A, Crawford, Dana C, Carrell, David S, Gerhard, Glenn S, Franklin, David P, Carey, David J, Phillips, Victoria L, Williams, Michael J A, Wei, Wenhua, Blair, Ross, Hill, Andrew A, Vasudevan, Thodor M, Lewis, David R, Thomson, Ian A, Krysa, Jo, Hill, Geraldine B, Roake, Justin, Merriman, Tony R, Oszkinis, Grzegorz, Galora, Silvia, Saracini, Claudia, Abbate, Rosanna, Pulli, Raffaele, Pratesi, Carlo, Saratzis, Athanasios, Verissimo, Ana R, Bumpstead, Suzannah, Badger, Stephen A, Clough, Rachel E, Cockerill, Gillian, Hafez, Hany, Scott, D Julian A, Futers, T Simon, Romaine, Simon P R, Bridge, Katherine, Griffin, Kathryn J, Bailey, Marc A, Smith, Alberto, Thompson, Matthew M, van Bockxmeer, Frank M, Matthiasson, Stefan E, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Blankensteijn, Jan D, Teijink, Joep A W, Wijmenga, Cisca, de Graaf, Jacqueline, Kiemeney, Lambertus A, Lindholt, Jes S, Hughes, Anne, Bradley, Declan T, Stirrups, Kathleen, Golledge, Jonathan, Norman, Paul E, Powell, Janet T, Humphries, Steve E, Hamby, Stephen E, Goodall, Alison H, Nelson, Christopher P, Sakalihasan, Natzi, Courtois, Audrey, Ferrell, Robert E, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Eicher, John D, Johnson, Andrew D, Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Schadt, Eric E, Björkegren, Johan L M, Lipovich, Leonard, Drolet, Anne M, Verhoeven, Eric L, Zeebregts, Clark J, Geelkerken, Robert H, van Sambeek, Marc R, van Sterkenburg, Steven M, de Vries, Jean-Paul, Stefansson, Kari, Thompson, John R, de Bakker, Paul I W, Deloukas, Panos, Sayers, Robert D, Harrison, Seamus C, van Rij, Andre M, Samani, Nilesh J, and Bown, Matthew J

Published
2017

21. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Author

Genetica Klinische Genetica, Circulatory Health, CMM Groep Kaaij, Brain, Infection & Immunity, Jones, Gregory T, Tromp, Gerard, Kuivaniemi, Helena, Gretarsdottir, Solveig, Baas, Annette F, Giusti, Betti, Strauss, Ewa, Van't Hof, Femke N G, Webb, Thomas R, Erdman, Robert, Ritchie, Marylyn D, Elmore, James R, Verma, Anurag, Pendergrass, Sarah, Kullo, Iftikhar J, Ye, Zi, Peissig, Peggy L, Gottesman, Omri, Verma, Shefali S, Malinowski, Jennifer, Rasmussen-Torvik, Laura J, Borthwick, Kenneth M, Smelser, Diane T, Crosslin, David R, de Andrade, Mariza, Ryer, Evan J, McCarty, Catherine A, Böttinger, Erwin P, Pacheco, Jennifer A, Crawford, Dana C, Carrell, David S, Gerhard, Glenn S, Franklin, David P, Carey, David J, Phillips, Victoria L, Williams, Michael J A, Wei, Wenhua, Blair, Ross, Hill, Andrew A, Vasudevan, Thodor M, Lewis, David R, Thomson, Ian A, Krysa, Jo, Hill, Geraldine B, Roake, Justin, Merriman, Tony R, Oszkinis, Grzegorz, Galora, Silvia, Saracini, Claudia, Abbate, Rosanna, Pulli, Raffaele, Pratesi, Carlo, Saratzis, Athanasios, Verissimo, Ana R, Bumpstead, Suzannah, Badger, Stephen A, Clough, Rachel E, Cockerill, Gillian, Hafez, Hany, Scott, D Julian A, Futers, T Simon, Romaine, Simon P R, Bridge, Katherine, Griffin, Kathryn J, Bailey, Marc A, Smith, Alberto, Thompson, Matthew M, van Bockxmeer, Frank M, Matthiasson, Stefan E, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Blankensteijn, Jan D, Teijink, Joep A W, Wijmenga, Cisca, de Graaf, Jacqueline, Kiemeney, Lambertus A, Lindholt, Jes S, Hughes, Anne, Bradley, Declan T, Stirrups, Kathleen, Golledge, Jonathan, Norman, Paul E, Powell, Janet T, Humphries, Steve E, Hamby, Stephen E, Goodall, Alison H, Nelson, Christopher P, Sakalihasan, Natzi, Courtois, Audrey, Ferrell, Robert E, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Eicher, John D, Johnson, Andrew D, Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Schadt, Eric E, Björkegren, Johan L M, Lipovich, Leonard, Drolet, Anne M, Verhoeven, Eric L, Zeebregts, Clark J, Geelkerken, Robert H, van Sambeek, Marc R, van Sterkenburg, Steven M, de Vries, Jean-Paul, Stefansson, Kari, Thompson, John R, de Bakker, Paul I W, Deloukas, Panos, Sayers, Robert D, Harrison, Seamus C, van Rij, Andre M, Samani, Nilesh J, Bown, Matthew J, Genetica Klinische Genetica, Circulatory Health, CMM Groep Kaaij, Brain, Infection & Immunity, Jones, Gregory T, Tromp, Gerard, Kuivaniemi, Helena, Gretarsdottir, Solveig, Baas, Annette F, Giusti, Betti, Strauss, Ewa, Van't Hof, Femke N G, Webb, Thomas R, Erdman, Robert, Ritchie, Marylyn D, Elmore, James R, Verma, Anurag, Pendergrass, Sarah, Kullo, Iftikhar J, Ye, Zi, Peissig, Peggy L, Gottesman, Omri, Verma, Shefali S, Malinowski, Jennifer, Rasmussen-Torvik, Laura J, Borthwick, Kenneth M, Smelser, Diane T, Crosslin, David R, de Andrade, Mariza, Ryer, Evan J, McCarty, Catherine A, Böttinger, Erwin P, Pacheco, Jennifer A, Crawford, Dana C, Carrell, David S, Gerhard, Glenn S, Franklin, David P, Carey, David J, Phillips, Victoria L, Williams, Michael J A, Wei, Wenhua, Blair, Ross, Hill, Andrew A, Vasudevan, Thodor M, Lewis, David R, Thomson, Ian A, Krysa, Jo, Hill, Geraldine B, Roake, Justin, Merriman, Tony R, Oszkinis, Grzegorz, Galora, Silvia, Saracini, Claudia, Abbate, Rosanna, Pulli, Raffaele, Pratesi, Carlo, Saratzis, Athanasios, Verissimo, Ana R, Bumpstead, Suzannah, Badger, Stephen A, Clough, Rachel E, Cockerill, Gillian, Hafez, Hany, Scott, D Julian A, Futers, T Simon, Romaine, Simon P R, Bridge, Katherine, Griffin, Kathryn J, Bailey, Marc A, Smith, Alberto, Thompson, Matthew M, van Bockxmeer, Frank M, Matthiasson, Stefan E, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Blankensteijn, Jan D, Teijink, Joep A W, Wijmenga, Cisca, de Graaf, Jacqueline, Kiemeney, Lambertus A, Lindholt, Jes S, Hughes, Anne, Bradley, Declan T, Stirrups, Kathleen, Golledge, Jonathan, Norman, Paul E, Powell, Janet T, Humphries, Steve E, Hamby, Stephen E, Goodall, Alison H, Nelson, Christopher P, Sakalihasan, Natzi, Courtois, Audrey, Ferrell, Robert E, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Eicher, John D, Johnson, Andrew D, Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Schadt, Eric E, Björkegren, Johan L M, Lipovich, Leonard, Drolet, Anne M, Verhoeven, Eric L, Zeebregts, Clark J, Geelkerken, Robert H, van Sambeek, Marc R, van Sterkenburg, Steven M, de Vries, Jean-Paul, Stefansson, Kari, Thompson, John R, de Bakker, Paul I W, Deloukas, Panos, Sayers, Robert D, Harrison, Seamus C, van Rij, Andre M, Samani, Nilesh J, and Bown, Matthew J

Published
2017

22. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Author

Jones, Gregory T, Tromp, Gerard, Kuivaniemi, Helena, Gretarsdottir, Solveig, Baas, Annette F, Giusti, Betti, Strauss, Ewa, Van't Hof, Femke N G, Webb, Thomas R, Erdman, Robert, Ritchie, Marylyn D, Elmore, James R, Verma, Anurag, Pendergrass, Sarah, Kullo, Iftikhar J, Ye, Zi, Peissig, Peggy L, Gottesman, Omri, Verma, Shefali S, Malinowski, Jennifer, Rasmussen-Torvik, Laura J, Borthwick, Kenneth M, Smelser, Diane T, Crosslin, David R, de Andrade, Mariza, Ryer, Evan J, McCarty, Catherine A, Böttinger, Erwin P, Pacheco, Jennifer A, Crawford, Dana C, Carrell, David S, Gerhard, Glenn S, Franklin, David P, Carey, David J, Phillips, Victoria L, Williams, Michael J A, Wei, Wenhua, Blair, Ross, Hill, Andrew A, Vasudevan, Thodor M, Lewis, David R, Thomson, Ian A, Krysa, Jo, Hill, Geraldine B, Roake, Justin, Merriman, Tony R, Oszkinis, Grzegorz, Galora, Silvia, Saracini, Claudia, Abbate, Rosanna, Pulli, Raffaele, Pratesi, Carlo, Saratzis, Athanasios, Verissimo, Ana R, Bumpstead, Suzannah, Badger, Stephen A, Clough, Rachel E, Cockerill, Gillian, Hafez, Hany, Scott, D Julian A, Futers, T Simon, Romaine, Simon P R, Bridge, Katherine, Griffin, Kathryn J, Bailey, Marc A, Smith, Alberto, Thompson, Matthew M, van Bockxmeer, Frank M, Matthiasson, Stefan E, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Blankensteijn, Jan D, Teijink, Joep A W, Wijmenga, Cisca, de Graaf, Jacqueline, Kiemeney, Lambertus A, Lindholt, Jes S, Hughes, Anne, Bradley, Declan T, Stirrups, Kathleen, Golledge, Jonathan, Norman, Paul E, Powell, Janet T, Humphries, Steve E, Hamby, Stephen E, Goodall, Alison H, Nelson, Christopher P, Sakalihasan, Natzi, Courtois, Audrey, Ferrell, Robert E, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Eicher, John D, Johnson, Andrew D, Betsholtz, Christer, Ruusalepp, Arno, Franzén, Oscar, Schadt, Eric E, Björkegren, Johan L M, Lipovich, Leonard, Drolet, Anne M, Verhoeven, Eric L, Zeebregts, Clark J, Geelkerken, Robert H, van Sambeek, Marc R, van Sterkenburg, Steven M, de Vries, J.P.P.M., Stefansson, Kari, Thompson, John R, de Bakker, Paul I W, Deloukas, Panos, Sayers, Robert D, Harrison, Seamus C, van Rij, Andre M, Samani, Nilesh J, Bown, Matthew J, Surgery, ICaR - Ischemia and repair, ACS - Microcirculation, and ACS - Atherosclerosis & ischemic syndromes

Subjects
Cardiac & Cardiovascular Systems, aortic aneurysm abdominal, computational biology, Cardiac and Cardiovascular Systems, genetics, Aortic Aneurysm, Abdominal/diagnosis, genome-wide association study, matrix metalloproteinases, meta-analysis, Aortic Aneurysm, Abdominal, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Physiology, Cardiology and Cardiovascular Medicine, Kardiologi, Hematology, C-REACTIVE PROTEIN, TRANSCRIPTION FACTORS, Genetic Variation/genetics, DENSITY-LIPOPROTEIN CHOLESTEROL, Genetic Loci/genetics, Genome-Wide Association Study/methods, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, abdominal, cardiovascular system, CORONARY-ARTERY-DISEASE, aortic aneurysm, Life Sciences & Biomedicine, aortic aneurysm, abdominal, SUSCEPTIBILITY LOCI, 1102 Cardiovascular Medicine And Haematology, Article, SDG 3 - Good Health and Well-being, Genetic Predisposition to Disease/epidemiology, Journal Article, CANDIDATE GENE ASSOCIATION, Hematologi, cardiovascular diseases, Science & Technology, genome-wide association study ■ matrix metalloproteinases, ELECTRONIC MEDICAL-RECORDS, HUMAN PREFRONTAL CORTEX, 1103 Clinical Sciences, Atherosclerosis, Peripheral Vascular Disease, Cardiovascular System & Hematology, SEQUENCE VARIANT, RECEPTOR-RELATED PROTEIN-1, Cardiovascular System & Cardiology, Clinical Track
Abstract

Supplemental Digital Content is available in the text., Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Published
2016

24. Update on Abdominal Aortic Aneurysm Research: From Clinical to Genetic Studies

Author

Kuivaniemi, Helena, Ryer, Evan J., Elmore, James R., Hinterseher, Irene, Smelser, Diane T., and Tromp, Gerard

Subjects
enzymes and coenzymes (carbohydrates), Article Subject, cardiovascular system, cardiovascular diseases, macromolecular substances, environment and public health
Abstract

An abdominal aortic aneurysm (AAA) is a dilatation of the abdominal aorta with a diameter of at least 3.0 cm. AAAs are often asymptomatic and are discovered as incidental findings in imaging studies or when the AAA ruptures leading to a medical emergency. AAAs are more common in males than females, in individuals of European ancestry, and in those over 65 years of age. Smoking is the most important environmental risk factor. In addition, a positive family history of AAA increases the person’s risk for AAA. Interestingly, diabetes has been shown to be a protective factor for AAA in many large studies. Hallmarks of AAA pathogenesis include inflammation, vascular smooth muscle cell apoptosis, extracellular matrix degradation, and oxidative stress. Autoimmunity may also play a role in AAA development and progression. In this Outlook paper, we summarize our recent studies on AAA including clinical studies related to surgical repair of AAA and genetic risk factor and large-scale gene expression studies. We conclude with a discussion on our research projects using large data sets available through electronic medical records and biobanks.

Published
2014
Full Text
View/download PDF

25. The Geisinger MyCode community health initiative: an electronic health record–linked biobank for precision medicine research

Author

Carey, David J., primary, Fetterolf, Samantha N., additional, Davis, F. Daniel, additional, Faucett, William A., additional, Kirchner, H. Lester, additional, Mirshahi, Uyenlinh, additional, Murray, Michael F., additional, Smelser, Diane T., additional, Gerhard, Glenn S., additional, and Ledbetter, David H., additional

Published
2016
Full Text
View/download PDF

28. Using HMORN’s Virtual Data Warehouse From Two Health Systems to Identify Risk Factors for Abdominal Aortic Aneurysm

Author

Smelser, Diane T, primary, Hirsch, Annemarie G, additional, Lewis, Meredith W, additional, Graham, Jove, additional, Hitz, Paul J, additional, McCarty, Catherine A, additional, Bock, Jonathan A, additional, Borthwick, Kenneth M, additional, Tromp, Gerardus, additional, Mowrey, Jacob, additional, Ryer, Evan, additional, and Elmore, James, additional

Published
2015
Full Text
View/download PDF

30. Genetic-based prediction of disease traits: prediction is very difficult, especially about the futureâ€

Author

Schrodi, Steven J., primary, Mukherjee, Shubhabrata, additional, Shan, Ying, additional, Tromp, Gerard, additional, Sninsky, John J., additional, Callear, Amy P., additional, Carter, Tonia C., additional, Ye, Zhan, additional, Haines, Jonathan L., additional, Brilliant, Murray H., additional, Crane, Paul K., additional, Smelser, Diane T., additional, Elston, Robert C., additional, and Weeks, Daniel E., additional

Published
2014
Full Text
View/download PDF

38. Association of varicose veins with rare protein-truncating variants in PIEZO1identified by exome sequencing of a large clinical population

Author

Smelser, Diane T., Haley, Jeremy S., Ryer, Evan J., Elmore, James R., Cook, Adam M., and Carey, David J.

Abstract

The present study sought to determine whether protein-truncating variants (PTVs) in PIEZO1and CASZ1genes, previously shown to be associated with varicose veins, were associated with an altered risk of varicose veins.

Published
2021
Full Text
View/download PDF

39. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K., Wilk, Jemma B., Morley, Michael P., Chaffin, Mark D., Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G., Ärnlöv, Johan, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Brandimarto, Jeffrey, Brown, Michael R., Buckbinder, Leonard, Carey, David J., Chasman, Daniel I., Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P., Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Dunn, Michael E., Engström, Gunnar, Esko, Tõnu, Felix, Stephan B., Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hyde, Craig L., Ingelsson, Erik, Jukema, J. Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian’an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B., März, Winfried, Melander, Olle, Mordi, Ify R., Morgan, Thomas, Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Niessner, Alexander, Niiranen, Teemu, O’Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N. A., Parry, Helen M., Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P. R., Rotter, Jerome I., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stender, Steen, Stott, David J., Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D., Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G., Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Waterworth, Dawn, Weeke, Peter E., Weiss, Raul, Wiggins, Kerri L., Xing, Heming, Yerges-Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J., McMurray, John J. V., Yang, Jian, Visscher, Peter M., Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A., Sattar, Naveed, Holmes, Michael V., Cappola, Thomas P., Asselbergs, Folkert W., Hingorani, Aroon D., Kuchenbaecker, Karoline, Ellinor, Patrick T., Lang, Chim C., Stefansson, Kari, Smith, J. Gustav, Vasan, Ramachandran S., Swerdlow, Daniel I., Lumbers, R. Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D., Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M., Habegger, Lukas, Hahn, Young, Hawes, Alicia, Van Hout, Cristopher, Jones, Marcus B., Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K., McCarthy, Shane, Mitnaul, Lyndon J., O’Dushlaine, Colm, Overton, John D., Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G., Schleicher, Thomas D., Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C., Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H., Widom, Louis, Wolf, Sarah E., Yadav, Ashish, and Ye, Bin

Subjects
2. Zero hunger, 631/443/592/2727, 631/208/205/2138, 692/699/75/230, 45/43, article, 692/308/174, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

40. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R. Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I., Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V., Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G., Asselin, Geraldine, Backman, Joshua D., Biggs, Mary L., Bloom, Heather L., Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R., Brunner‐La Rocca, Hans‐Peter, Carey, David J., Chaffin, Mark D., Chasman, Daniel I., Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H., Chutkow, William, Cleland, John G.F., Cook, James P., De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E., Denaxas, Spiros, Doney, Alexander S., Dörr, Marcus, Dudley, Samuel C., Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B., Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S., Gross, Stefan, Guðbjartsson, Daníel F., Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M., Van Der Harst, Pim, Hedman, Åsa K., Helgadottir, Anna, Hillege, Hans, Hyde, Craig L., Jacob, Jaison, Jukema, J. Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay‐Tee, Kleber, Marcus E., Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M., London, Barry, Lotta, Luca A., Lovering, Ruth C., Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B., Marston, Nicholas A., März, Winfried, McMurray, John J.V., Melander, Olle, Melloni, Giorgio, Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morrison, Alanna C., Nagle, Michael W., Nelson, Christopher P., Newton‐Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L., Owens, Anjali T., Palmer, Colin N.A., Paré, Guillaume, Perola, Markus, Perreault, Louis‐Philippe Lemieux, Portilla‐Fernandez, Eliana, Psaty, Bruce M., Rice, Kenneth M., Ridker, Paul M., Romaine, Simon P.R., Roselli, Carolina, Rotter, Jerome I., Ruff, Christian T., Sabatine, Marc S., Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A., Smelser, Diane T., Smith, Nicholas L., Stefansson, Kari, Stender, Steen, Stott, David J., Sveinbjörnsson, Garðar, Tammesoo, Mari‐Liis, Tardif, Jean‐Claude, Taylor, Kent D., Teder‐Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp‐Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G., Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M., Völker, Uwe, Voors, Adriaan A., Wang, Xiaosong, Wareham, Nicholas J., Weeke, Peter E., Weiss, Raul, White, Harvey D., Wiggins, Kerri L., Xing, Heming, Yang, Jian, Yang, Yifan, Yerges‐Armstrong, Laura M., Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B., Holm, Hilma, Sattar, Naveed, Lubitz, Steven A., Lanfear, David E., Shah, Svati, Dunn, Michael E., Wells, Quinn S., Asselbergs, Folkert W., Hingorani, Aroon D., Dubé, Marie‐Pierre, Samani, Nilesh J., Lang, Chim C., Cappola, Thomas P., Ellinor, Patrick T., Vasan, Ramachandran S., and Smith, J. Gustav

Subjects
Study Design, Cardiomyopathy, FOS: Biological sciences, Study Designs, Genetics, Heart failure, Biomarkers, 3. Good health, Association studies
Abstract

Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063, Funder: Swedish National Health Service, Funder: Skåne University Hospital; Id: http://dx.doi.org/10.13039/501100011077, Funder: Crafoord Foundation; Id: http://dx.doi.org/10.13039/501100003173, Funder: Department of Medicine, Boston University School of Medicine; Id: http://dx.doi.org/10.13039/100008748, Funder: Evans Medical Foundation; Id: http://dx.doi.org/10.13039/100015927, Funder: National Heart, Lung, and Blood Institute; Id: http://dx.doi.org/10.13039/100000050, Funder: British Heart Foundation Cardiovascular Biomedicine, Funder: NIHR UCLH Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100012317, Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

41. The genomics of heart failure: design and rationale of the HERMES consortium

Author

Lumbers, R Thomas, Shah, Sonia, Lin, Honghuang, Czuba, Tomasz, Henry, Albert, Swerdlow, Daniel I, Mälarstig, Anders, Andersson, Charlotte, Verweij, Niek, Holmes, Michael V, Ärnlöv, Johan, Svensson, Per, Hemingway, Harry, Sallah, Neneh, Almgren, Peter, Aragam, Krishna G, Asselin, Geraldine, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Boersma, Eric, Brandimarto, Jeffrey, Brown, Michael R, Brunner-La Rocca, Hans-Peter, Carey, David J, Chaffin, Mark D, Chasman, Daniel I, Chazara, Olympe, Chen, Xing, Chen, Xu, Chung, Jonathan H, Chutkow, William, Cleland, John GF, Cook, James P, De Denus, Simon, Dehghan, Abbas, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Engström, Gunnar, Esko, Tõnu, Fatemifar, Ghazaleh, Felix, Stephan B, Finan, Chris, Ford, Ian, Fougerousse, Francoise, Fouodjio, René, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gui, Hongsheng, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hedman, Åsa K, Helgadottir, Anna, Hillege, Hans, Hyde, Craig L, Jacob, Jaison, Jukema, J Wouter, Kamanu, Frederick, Kardys, Isabella, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Kraus, Bill, Kuchenbaecker, Karoline, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Mann, Douglas, Margulies, Kenneth B, Marston, Nicholas A, März, Winfried, McMurray, John JV, Melander, Olle, Melloni, Giorgio, Mordi, Ify R, Morley, Michael P, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Newton-Cheh, Christopher, Niessner, Alexander, Niiranen, Teemu, Nowak, Christoph, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Paré, Guillaume, Perola, Markus, Perreault, Louis-Philippe Lemieux, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Roselli, Carolina, Rotter, Jerome I, Ruff, Christian T, Sabatine, Marc S, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stefansson, Kari, Stender, Steen, Stott, David J, Sveinbjörnsson, Garðar, Tammesoo, Mari-Liis, Tardif, Jean-Claude, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tuckwell, Danny, Tyl, Benoit, Uitterlinden, Andre G, Vaura, Felix, Veluchamy, Abirami, Visscher, Peter M, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Weeke, Peter E, Weiss, Raul, White, Harvey D, Wiggins, Kerri L, Xing, Heming, Yang, Jian, Yang, Yifan, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Faye, Regeneron Genetics Center, Wilk, Jemma B, Holm, Hilma, Sattar, Naveed, Lubitz, Steven A, Lanfear, David E, Shah, Svati, Dunn, Michael E, Wells, Quinn S, Asselbergs, Folkert W, Hingorani, Aroon D, Dubé, Marie-Pierre, Samani, Nilesh J, Lang, Chim C, Cappola, Thomas P, Ellinor, Patrick T, Vasan, Ramachandran S, and Smith, J Gustav

Subjects
Aged, 80 and over, Heart Failure, Male, Cardiomyopathy, Genomics, Middle Aged, 16. Peace & justice, Prognosis, 3. Good health, FOS: Biological sciences, Genetics, Humans, Female, Biomarkers, Association studies, Aged, Genome-Wide Association Study
Abstract

AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10-8 under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

42. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin N A, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon P R, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John J V, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, 3. Good health
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

43. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, Van Der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, Van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Völker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, and Lumbers, R Thomas

Subjects
2. Zero hunger, Cyclin-Dependent Kinase Inhibitor p21, Heart Failure, Microfilament Proteins, Muscle Proteins, Coronary Artery Disease, Mendelian Randomization Analysis, Ventricular Function, Left, 3. Good health, Risk Factors, Case-Control Studies, Atrial Fibrillation, Humans, Apoptosis Regulatory Proteins, Cardiomyopathies, Carrier Proteins, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

44. Prevalence and Electronic Health Record-Based Phenotype of Loss-of-Function Genetic Variants in Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes

Author

Carruth, Eric D., Young, Wilson, Beer, Dominik, James, Cynthia A., Calkins, Hugh, Jing, Linyuan, Raghunath, Sushravya, Hartzel, Dustin N., Leader, Joseph B., Kirchner, H. Lester, Smelser, Diane T., Carey, David J., Kelly, Melissa A., Sturm, Amy C., Alsaid, Amro, Fornwalt, Brandon K., and Haggerty, Christopher M.

Abstract

Supplemental Digital Content is available in the text.

Published
2019
Full Text
View/download PDF

45. A COMPARISON OF OBESITY CANDIDATE GENES IN THE ANABOLIC NEUROPEPTIDE PATHWAY IN THE SAMOAN AND AMERICAN SAMOAN POPULATIONS

Author

SMELSER, DIANE T.

Subjects
Health Sciences, Public Health, Obesity, Samoan Population, Anabolic Neuropeptide Pathway, Candidate Gene Association Study, Neuropeptide Y
Abstract

Obesity is a significant public health problem with substantial morbidity and mortality costs, increasing at an alarming rate. The literature suggests that obesity is a complex genetic disorder, influenced by environmental factors. The Samoan Islands represent an isolated population that recently divided into two polities, American Samoa and the independent nation of Samoa. Although genetically similar, these two populations differ significantly in their prevalence of obesity and lifestyle. The American Samoans and Samoans have a very high rate of obesity, 84% in women and 78% in men in America Samoa; and 59% for women and 29% for men in Samoa. The American Samoans have taken on a modern lifestyle and diet while the Samoans remain traditional in their lifestyle and diet. This is the ideal population to conduct a candidate gene association study. The Samoans migrated from Southeast Asia, facing periods of feast and famine. The “thrifty genotype” (as proposed by James Neel) would allow the Samoan individuals with high fat storage and decreased metabolism to survive, and pass those genes on to the next generation. Therefore, a candidate gene study focusing on those thrifty genes might identify an association with obesity in the Samoan populations. The anabolic neuropeptide pathway functions to increase stores of body fat while decreasing metabolic rate, and eight key genes from this pathway were selected for this study. A group of 454 American Samoan and 536 Samoan individuals were genotyped for single nucleotide polymorphisms (SNPs) within each gene. Only the neuropeptide Y gene was significant on an allelic, genotypic and haplotypic basis. Resistin also showed statistical significance when the obese individuals were compared on the haplotype level. Multivariate regression analysis was used to include the plasma levels of insulin, glucose and leptin, as well as systolic and diastolic blood pressure and smoking. Insulin, glucose, leptin and diastolic blood pressure were all significant with various SNPs when intervening variables were taken into account. Differences in the genotypes of the candidate genes coupled with the variation in lifestyle between these two Samoan populations, may explain the difference in obesity levels and provide clues for further obesity research.

Published
2006

46. Development of a Polygenic Risk Score to Predict Diverticulitis.

Author

Schaeffer HD, Smelser DT, Rao HS, Haley JS, Long KC, Slipak SH, Carey DJ, and Hoffman RL

Subjects
Humans, Genetic Risk Score, Genome-Wide Association Study, Biological Specimen Banks, Diverticulitis, Colonic diagnosis, Diverticulitis, Colonic epidemiology, Diverticulitis, Colonic genetics, Diverticulitis diagnosis, Diverticulitis epidemiology, Diverticulitis genetics, Diverticulum complications, Diverticular Diseases complications
Abstract

Background: Despite its prevalence and associated morbidity, we remain limited in our ability to predict the course of a patient with diverticular disease. Although several clinical and genetic risk factors have been identified, we do not know how these factors relate to one another., Objective: Our aim was to determine whether a polygenic risk score could improve risk prediction for diverticulitis and recurrent diverticulitis compared with a model using only clinical factors., Design: This is an observational study., Setting: The study examines the predictive ability of a polygenic risk score for diverticulitis developed using prior genome-wide association studies and validated using the MyCode biobank., Patients: This study included patients of European ancestry in the Geisinger Health System who were enrolled in the MyCode Community Health biobanking program., Main Outcome Measures: The ability of a polygenic risk score to predict diverticulosis, diverticulitis, and recurrent diverticulitis was the main outcome measure of this study., Results: A total of 60,861 patients were included, of whom 9912 (16.3%) had diverticulosis or diverticulitis (5015 with diverticulosis and 4897 with diverticulitis). When divided into deciles, our polygenic risk score stratified patients by risk of both diverticulosis and diverticulitis with a 2-fold difference in disease risk between the highest and lowest deciles for diverticulitis and a 4.8-fold difference for recurrent complicated diverticulitis. When compared with clinical factors alone, our polygenic risk score was able to improve risk prediction of recurrent diverticulitis., Limitations: Our population is largely located in a single geographic region and were classified by disease status, using international classification of diseases codes., Conclusions: This predictive model stratifies patients based on genetic risk for diverticular disease. The increased frequency of recurrent disease in our high-risk patients suggests that a polygenic risk score, in addition to other factors, may help guide the discussion regarding surgical intervention. See Video Abstract ., Desarrollo De Una Puntuacin De Riesgo Polignico Para Predecir La Diverticulitis: ANTECEDENTES:A pesar de su prevalencia y morbilidad asociada, nuestra capacidad para predecir el curso en un paciente con enfermedad diverticular sigue siendo limitada. Si bien se han identificado varios factores de riesgo clínicos y genéticos, no sabemos cómo se relacionan estos factores entre sí.OBJETIVO:Determinar si una puntuación de riesgo poligénico podría mejorar la predicción del riesgo de diverticulitis y diverticulitis recurrente en comparación con un modelo que utiliza solo factores clínicos.DISEÑO:Un estudio observacional que examina la capacidad predictiva de una puntuación de riesgo poligénico para la diverticulitis desarrollada usando estudios previos de asociación amplia del genoma y validada usando el biobanco MyCode.ÁMBITOS Y PACIENTES:Pacientes de ascendencia europea en el Sistema de Salud Geisinger que estaban inscritos en el programa de biobancos MyCode Community Health.PRINCIPALES MEDIDAS DE VALORACIÓN:La capacidad de una puntuación de riesgo poligénico para predecir diverticulosis, diverticulitis y diverticulitis recurrente.RESULTADOS:Se incluyeron un total de 60.861 pacientes, de los cuales 9.912 (16,3%) presentaban diverticulosis o diverticulitis (5.015 con diverticulosis y 4.897 con diverticulitis). Cuando se dividió en deciles, nuestra puntuación de riesgo poligénico estratificó a los pacientes según el riesgo de diverticulosis y diverticulitis con una diferencia de 2 veces en el riesgo de enfermedad entre los deciles más alto y más bajo para diverticulitis y una diferencia de 4,8 veces para diverticulitis complicada recurrente. En comparación con los factores clínicos solos, nuestra puntuación de riesgo poligénico pudo mejorar la predicción del riesgo de diverticulitis recurrente.LIMITACIONES:Nuestra población se encuentra en gran parte en una sola región geográfica y se clasificó por estado de enfermedad utilizando códigos de clasificación internacional de enfermedades.CONCLUSIONES:Este modelo predictivo estratifica a los pacientes en función del riesgo genético de enfermedad diverticular. La mayor frecuencia de enfermedad recurrente en nuestros pacientes de alto riesgo sugiere que un puntaje de riesgo poligénico, además de otros factores, puede ayudar a guiar la discusión sobre la intervención quirúrgica. (Traducción- Dr. Ingrid Melo )., (Copyright © The ASCRS 2023.)

Published
2024
Full Text
View/download PDF

47. The genomics of heart failure: design and rationale of the HERMES consortium.

Author

Lumbers RT, Shah S, Lin H, Czuba T, Henry A, Swerdlow DI, Mälarstig A, Andersson C, Verweij N, Holmes MV, Ärnlöv J, Svensson P, Hemingway H, Sallah N, Almgren P, Aragam KG, Asselin G, Backman JD, Biggs ML, Bloom HL, Boersma E, Brandimarto J, Brown MR, Brunner-La Rocca HP, Carey DJ, Chaffin MD, Chasman DI, Chazara O, Chen X, Chen X, Chung JH, Chutkow W, Cleland JGF, Cook JP, de Denus S, Dehghan A, Delgado GE, Denaxas S, Doney AS, Dörr M, Dudley SC, Engström G, Esko T, Fatemifar G, Felix SB, Finan C, Ford I, Fougerousse F, Fouodjio R, Ghanbari M, Ghasemi S, Giedraitis V, Giulianini F, Gottdiener JS, Gross S, Guðbjartsson DF, Gui H, Gutmann R, Haggerty CM, van der Harst P, Hedman ÅK, Helgadottir A, Hillege H, Hyde CL, Jacob J, Jukema JW, Kamanu F, Kardys I, Kavousi M, Khaw KT, Kleber ME, Køber L, Koekemoer A, Kraus B, Kuchenbaecker K, Langenberg C, Lind L, Lindgren CM, London B, Lotta LA, Lovering RC, Luan J, Magnusson P, Mahajan A, Mann D, Margulies KB, Marston NA, März W, McMurray JJV, Melander O, Melloni G, Mordi IR, Morley MP, Morris AD, Morris AP, Morrison AC, Nagle MW, Nelson CP, Newton-Cheh C, Niessner A, Niiranen T, Nowak C, O'Donoghue ML, Owens AT, Palmer CNA, Paré G, Perola M, Perreault LL, Portilla-Fernandez E, Psaty BM, Rice KM, Ridker PM, Romaine SPR, Roselli C, Rotter JI, Ruff CT, Sabatine MS, Salo P, Salomaa V, van Setten J, Shalaby AA, Smelser DT, Smith NL, Stefansson K, Stender S, Stott DJ, Sveinbjörnsson G, Tammesoo ML, Tardif JC, Taylor KD, Teder-Laving M, Teumer A, Thorgeirsson G, Thorsteinsdottir U, Torp-Pedersen C, Trompet S, Tuckwell D, Tyl B, Uitterlinden AG, Vaura F, Veluchamy A, Visscher PM, Völker U, Voors AA, Wang X, Wareham NJ, Weeke PE, Weiss R, White HD, Wiggins KL, Xing H, Yang J, Yang Y, Yerges-Armstrong LM, Yu B, Zannad F, Zhao F, Wilk JB, Holm H, Sattar N, Lubitz SA, Lanfear DE, Shah S, Dunn ME, Wells QS, Asselbergs FW, Hingorani AD, Dubé MP, Samani NJ, Lang CC, Cappola TP, Ellinor PT, Vasan RS, and Smith JG

Subjects
Aged, Aged, 80 and over, Female, Genomics, Humans, Male, Middle Aged, Prognosis, Genome-Wide Association Study, Heart Failure genetics
Abstract

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure., Methods and Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 -8 under an additive genetic model., Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Published
2021
Full Text
View/download PDF

48. Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation.

Author

Choi SH, Weng LC, Roselli C, Lin H, Haggerty CM, Shoemaker MB, Barnard J, Arking DE, Chasman DI, Albert CM, Chaffin M, Tucker NR, Smith JD, Gupta N, Gabriel S, Margolin L, Shea MA, Shaffer CM, Yoneda ZT, Boerwinkle E, Smith NL, Silverman EK, Redline S, Vasan RS, Burchard EG, Gogarten SM, Laurie C, Blackwell TW, Abecasis G, Carey DJ, Fornwalt BK, Smelser DT, Baras A, Dewey FE, Jaquish CE, Papanicolaou GJ, Sotoodehnia N, Van Wagoner DR, Psaty BM, Kathiresan S, Darbar D, Alonso A, Heckbert SR, Chung MK, Roden DM, Benjamin EJ, Murray MF, Lunetta KL, Lubitz SA, and Ellinor PT

Subjects
Adult, Age of Onset, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heterozygote, Humans, Male, Middle Aged, Quality Control, Atrial Fibrillation genetics, Connectin genetics, Loss of Function Mutation
Abstract

Importance: Atrial fibrillation (AF) is the most common arrhythmia affecting 1% of the population. Young individuals with AF have a strong genetic association with the disease, but the mechanisms remain incompletely understood., Objective: To perform large-scale whole-genome sequencing to identify genetic variants related to AF., Design, Setting, and Participants: The National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine Program includes longitudinal and cohort studies that underwent high-depth whole-genome sequencing between 2014 and 2017 in 18 526 individuals from the United States, Mexico, Puerto Rico, Costa Rica, Barbados, and Samoa. This case-control study included 2781 patients with early-onset AF from 9 studies and identified 4959 controls of European ancestry from the remaining participants. Results were replicated in the UK Biobank (346 546 participants) and the MyCode Study (42 782 participants)., Exposures: Loss-of-function (LOF) variants in genes at AF loci and common genetic variation across the whole genome., Main Outcomes and Measures: Early-onset AF (defined as AF onset in persons <66 years of age). Due to multiple testing, the significance threshold for the rare variant analysis was P = 4.55 × 10-3., Results: Among 2781 participants with early-onset AF (the case group), 72.1% were men, and the mean (SD) age of AF onset was 48.7 (10.2) years. Participants underwent whole-genome sequencing at a mean depth of 37.8 fold and mean genome coverage of 99.1%. At least 1 LOF variant in TTN, the gene encoding the sarcomeric protein titin, was present in 2.1% of case participants compared with 1.1% in control participants (odds ratio [OR], 1.76 [95% CI, 1.04-2.97]). The proportion of individuals with early-onset AF who carried a LOF variant in TTN increased with an earlier age of AF onset (P value for trend, 4.92 × 10-4), and 6.5% of individuals with AF onset prior to age 30 carried a TTN LOF variant (OR, 5.94 [95% CI, 2.64-13.35]; P = 1.65 × 10-5). The association between TTN LOF variants and AF was replicated in an independent study of 1582 patients with early-onset AF (cases) and 41 200 control participants (OR, 2.16 [95% CI, 1.19-3.92]; P = .01)., Conclusions and Relevance: In a case-control study, there was a statistically significant association between an LOF variant in the TTN gene and early-onset AF, with the variant present in a small percentage of participants with early-onset AF (the case group). Further research is necessary to understand whether this is a causal relationship.

Published
2018
Full Text
View/download PDF

49. ePhenotyping for Abdominal Aortic Aneurysm in the Electronic Medical Records and Genomics (eMERGE) Network: Algorithm Development and Konstanz Information Miner Workflow.

Author

Borthwick KM, Smelser DT, Bock JA, Elmore JR, Ryer EJ, Ye Z, Pacheco JA, Carrell DS, Michalkiewicz M, Thompson WK, Pathak J, Bielinski SJ, Denny JC, Linneman JG, Peissig PL, Kho AN, Gottesman O, Parmar H, Kullo IJ, McCarty CA, Böttinger EP, Larson EB, Jarvik GP, Harley JB, Bajwa T, Franklin DP, Carey DJ, Kuivaniemi H, and Tromp G

Abstract

Background and Objective: We designed an algorithm to identify abdominal aortic aneurysm cases and controls from electronic health records to be shared and executed within the "electronic Medical Records and Genomics" (eMERGE) Network., Materials and Methods: Structured Query Language, was used to script the algorithm utilizing "Current Procedural Terminology" and "International Classification of Diseases" codes, with demographic and encounter data to classify individuals as case, control, or excluded. The algorithm was validated using blinded manual chart review at three eMERGE Network sites and one non-eMERGE Network site. Validation comprised evaluation of an equal number of predicted cases and controls selected at random from the algorithm predictions. After validation at the three eMERGE Network sites, the remaining eMERGE Network sites performed verification only. Finally, the algorithm was implemented as a workflow in the Konstanz Information Miner, which represented the logic graphically while retaining intermediate data for inspection at each node. The algorithm was configured to be independent of specific access to data and was exportable (without data) to other sites., Results: The algorithm demonstrated positive predictive values (PPV) of 92.8% (CI: 86.8-96.7) and 100% (CI: 97.0-100) for cases and controls, respectively. It performed well also outside the eMERGE Network. Implementation of the transportable executable algorithm as a Konstanz Information Miner workflow required much less effort than implementation from pseudo code, and ensured that the logic was as intended., Discussion and Conclusion: This ePhenotyping algorithm identifies abdominal aortic aneurysm cases and controls from the electronic health record with high case and control PPV necessary for research purposes, can be disseminated easily, and applied to high-throughput genetic and other studies.

Published
2015

Catalog

Books, media, physical & digital resources
See catalog results