Essential hypertension [EHYT] reaches epidemic proportions among adults and is a significant risk factor for premature coronary artery disease [CAD] and stroke. The overall objective of this revised proposal is to localize individual genes, called blood pressure quantitative train genes [BPQTGs], which influence blood pressure levels in the population-at- large, and to determine if these genes are able to predict the occurrence of EHYT or CAD. This project will make use of previously collected DNA and clinical data from members of 573 randomly-ascertained multigeneration pedigrees from the Rochester Family Heart Study. Two complementary research strategies will be used to located BPQTGs.
Aim 1 will use robust sibling pair linkage methods, parental marker data, and office BP levels measured on 1,376 full sibling pairs to localize BPQTGs to regions of the human genome marked by highly polymorphic tandem repeat loci in or very near to 59 genes involved in BP regulation. These genes were selected based on their involvement in the renin/angiotensin system, ion transport, cardiac physiology, biometabolism of neurotransmitters, or carbohydrate and lipid metabolism. At each gene, a highly polymorphic tandem repeat marker locus has already been identified.
Aim 2 will use methods of association analysis for related individuals and office BP levels measured on 587 full sibships to localize BPQTGs to regions of the human genome marked by the 59 candidate BPQTGs.
Aim 3 will determine if variation in these BPQTGs improves the ability to predict differences in BP levels in a sample of 1,166 unrelated normotensive adults of EHYT status in a sample of 1,160 unrelated grandparents beyond that provided by established predictors.
Aim 4 will determine if variation in these BPQTGs improves the ability to predict symptomatic or asymptomatic CAD status beyond that provided by established predictors including BP and EHYT.
Aims 3 and 4 will also ask whether the predictive relationship of the traditional risk factors to BP, EHYT, or CAD is different among genotypes at these BPQTGs. The research proposed here to localize BPQTGs represents an initial step toward applying DNA information to early identification of at-risk individuals and understanding the complex relationship between BP, EHYT and CAD.
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