In this proposal, we will employ several synergistic strategies to identify novel genetic determinants of hypertension. Our primary strategy will be to use genomic markers (both anonymous markers and candidate genes) spanning the human genome at an average density of 10 cM to examine 250 white sibships in Tecumseh, MI for genetic linkage with blood pressure and the intermediate phenotypic features of elevated erythrocyte lithium- sodium countertransport, the hyperkinetic hyperadrenergic state, decreased proximal tubular lithium clearance (a measure of proximal tubular sodium handling), and elements of the renin-angiotensin system (plasma renin and angiotensin-converting enzyme activity and serum angiotensinogen concentration). Positive findings will be confirmed by further testing for linkage in a population of 250 African-American sibships in Maywood, IL. In addition, we will seek to develop new candidate genes for hypertension by identifying genes linked to the hypertensive phenotype in segregating rat populations derived from inbred normotensive and hypertensive strains; homologues of genes identified in rats will be searched for in humans. Having developed and refined important candidates in our sibships and rat models, we will test associations in several extant black populations in Jamaica and Nigeria as well as in subjects in Tecumseh and Maywood selected from the extremes of the populational blood pressure distribution. To carry out these investigations, we have brought together well- characterized population resources suitable for the identification of probands and families affected by hypertension (Tecumseh, MI and Maywood, IL), two experienced teams of epidemiological investigators at the University of Michigan and Loyola University of Chicago, state-of-the-art genotyping facilities run by experienced investigators at Case Western Reserve University, a superb team of statistical geneticists, an animal resource with a proven record of productivity in identifying genetic loci regulating blood pressure in hypertensive rats, and several relevant population resources suitable for case-control studies (Nigeria, Jamaica). We are confident that these resources will permit us to accomplish our primary aim of identifying genetic determinants of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
1U10HL054512-01
Application #
2232876
Study Section
Special Emphasis Panel (ZHL1-CCT-M (F2))
Project Start
1995-09-05
Project End
2000-08-31
Budget Start
1995-09-05
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Sinner, Moritz F; Tucker, Nathan R; Lunetta, Kathryn L et al. (2014) Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation. Circulation 130:1225-35
Wain, Louise V (see original citation for additional authors) (2011) Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet 43:1005-11
International Consortium for Blood Pressure Genome-Wide Association Studies (see original citation for additional authors) (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103-9
Simino, Jeannette; Shi, Gang; Kume, Rezart et al. (2011) Five blood pressure loci identified by an updated genome-wide linkage scan: meta-analysis of the Family Blood Pressure Program. Am J Hypertens 24:347-54
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Nolte, Ilja M; Wallace, Chris; Newhouse, Stephen J et al. (2009) Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. PLoS One 4:e6138

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