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 #
2R01HL086694-04A1
Application #
8185912
Study Section
Special Emphasis Panel (ZRG1-PSE-J (03))
Program Officer
Paltoo, Dina
Project Start
2006-12-01
Project End
2014-05-31
Budget Start
2011-08-05
Budget End
2012-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$4,005,378
Indirect Cost
Name
Johns Hopkins University
Department
Genetics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
McKeown, Nicola M; Dashti, Hassan S; Ma, Jiantao et al. (2018) Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis. Diabetologia 61:317-330
Sarnowski, Chloé; Kavousi, Maryam; Isaacs, Steve et al. (2018) Genetic variants associated with earlier age at menopause increase the risk of cardiovascular events in women. Menopause 25:451-457
Rudra, Pratyaydipta; Broadaway, K Alaine; Ware, Erin B et al. (2018) Testing cross-phenotype effects of rare variants in longitudinal studies of complex traits. Genet Epidemiol 42:320-332
Lee, Dongwon; Kapoor, Ashish; Safi, Alexias et al. (2018) Human cardiac cis-regulatory elements, their cognate transcription factors, and regulatory DNA sequence variants. Genome Res 28:1577-1588
Ashar, Foram N; Mitchell, Rebecca N; Albert, Christine M et al. (2018) A comprehensive evaluation of the genetic architecture of sudden cardiac arrest. Eur Heart J 39:3961-3969
Prins, Bram P; Mead, Timothy J; Brody, Jennifer A et al. (2018) Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biol 19:87
Keaton, Jacob M; Gao, Chuan; Guan, Meijian et al. (2018) Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans. Genet Epidemiol 42:559-570
Fernández-Rhodes, Lindsay; Malinowski, Jennifer R; Wang, Yujie et al. (2018) The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis. PLoS One 13:e0200486
Weng, Lu-Chen; Guan, Weihua; Steffen, Lyn M et al. (2018) Pleiotropic effects of n-6 and n-3 fatty acid-related genetic variants on circulating hemostatic variables. Thromb Res 168:53-59
Hong, Jaeyoung; Hatchell, Kathryn E; Bradfield, Jonathan P et al. (2018) Transethnic Evaluation Identifies Low-Frequency Loci Associated With 25-Hydroxyvitamin D Concentrations. J Clin Endocrinol Metab 103:1380-1392

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