Despite decades of research on blood pressure (BP) physiology, our understanding of the biological basis of clinical hypertension (HTN) is still wanting. Recent, genome-wide association studies (GWAS) in ~70,000 individuals of European ancestry have been successful in identifying common variants at 29 loci that explain 2.5% of the inter-individual variation in systolic- (SBP) and diastolic- (DBP) blood pressure, with concomitant effects on HTN. Similar studies are ongoing using pulse (PP) and mean arterial (MAP) pressure. These putative genes provide new targets for understanding essential hypertension but the vast majority of the genetic variation in HTN susceptibility remains elusive. We propose a comprehensive study to explore the role of rare and common genomic variation on SBP, DBP and HTN in individuals of European (EA) and African (AA) American ancestry using contemporary genomic methods including exome sequencing and novel statistical methods that include gene-gene and gene-environment interactions. This study includes DNA samples, genotypes and phenotypes from the ARIC (Atherosclerosis Risk in Communities), FBPP (Family Blood Pressure Program), WHI (Women's Health Initiative) and CARDIA (Coronary Artery Risk Development In Young Adults) cohorts, with replication of findings using data and meta-analysis from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), CARe (Candidate-gene Association Resource), ICBP (International Consortium of Blood Pressure GWAS) and RFGEH (Research Program in Genes, Environment and Health) consortia/studies. We will explore: (1) A third generation BP and HTN GWAS using all known polymorphic markers;(2) a first generation BP and HTN EWAS (exome-wide association study) using all identifiable rare variants;and, (3) gene-gene and gene-environment interactions in BP and HTN variability. !

Public Health Relevance

Genome-wide association studies for the different blood pressure traits, that are intermediate phenotypes for essential hypertension and its consequences for target organ damage, have recently been successful with 29 loci identified but explaining only 2.5% of the phenotypic variance upon meta-analyses of 70,000 samples of European ancestry. In this proposal, we conduct computational and molecular genetic experiments to increase gene discovery by studying all polymorphisms in the human genome, assessing the role of rare variants in the exome and the role of gene- environment interactions. Our aims are to improve the molecular genetic understanding of blood pressure regulation and inter-individual variation on hypertension risk.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086694-05
Application #
8310976
Study Section
Special Emphasis Panel (ZRG1-PSE-J (03))
Program Officer
Applebaum-Bowden, Deborah
Project Start
2006-12-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$4,013,092
Indirect Cost
$508,563
Name
Johns Hopkins University
Department
Genetics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Tajuddin, Salman M; Schick, Ursula M; Eicher, John D et al. (2016) Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. Am J Hum Genet 99:22-39
de Vries, Paul S; Chasman, Daniel I; Sabater-Lleal, Maria et al. (2016) A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. Hum Mol Genet 25:358-70
Allen, Norrina B; Lloyd-Jones, Donald; Hwang, Shih-Jen et al. (2016) Genetic loci associated with ideal cardiovascular health: A meta-analysis of genome-wide association studies. Am Heart J 175:112-20
Scott, Robert A; Freitag, Daniel F; Li, Li et al. (2016) A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Sci Transl Med 8:341ra76
Yu, Bing; Pulit, Sara L; Hwang, Shih-Jen et al. (2016) Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. Circ Cardiovasc Genet 9:64-70
Yu, Bing; de Vries, Paul S; Metcalf, Ginger A et al. (2016) Whole genome sequence analysis of serum amino acid levels. Genome Biol 17:237
Cade, Brian E; Gottlieb, Daniel J; Lauderdale, Diane S et al. (2016) Common variants in DRD2 are associated with sleep duration: the CARe consortium. Hum Mol Genet 25:167-79
Rasheed, Humaira; McKinney, Cushla; Stamp, Lisa K et al. (2016) The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets. PLoS One 11:e0147939
Broadaway, K Alaine; Cutler, David J; Duncan, Richard et al. (2016) A Statistical Approach for Testing Cross-Phenotype Effects of Rare Variants. Am J Hum Genet 98:525-40
Kapoor, Ashish; Bakshy, Kiranmayee; Xu, Linda et al. (2016) Rare coding TTN variants are associated with electrocardiographic QT interval in the general population. Sci Rep 6:28356

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