Defining the genetic architecture of hypertension remains a central challenge for cardiovascular epidemiology. Technical and analytic advances have now created a clear strategy that can be used to move toward that goal. In the 2 completed grant cycles, over 12,000 participants, including family members and unrelated cases/controls, have been recruited from communities in Nigeria, Jamaica and the US. Significant linkage results have been obtained and candidate genes/pathways have been extensively evaluated. In this application we propose to continue a study of the genetics of hypertension in populations of West African origin and attempt positional cloning of susceptibility genes. The goals of this project are: 1. Supplement evidence on chromosomes 6, 7 and 11 (MLODs 2.7 - 3.8) with a new set of dense markers; search for positional candidate genes for hypertension at the two best regions. Confirm the linkage evidence found in our current sample with additional markers, narrow the interval and attempt to replicate this evidence of linkage in a sample of 1,689 individuals. 2) Identify the genes under the linkage peak(s), find appropriate single nucleotide polymorphisms (SNPs) with frequency > 10% and conduct association/linkage disequilibrium mapping. 3). Replicate these findings in additional case-control studies and assess potential gene-environment interactions. The investigators on this application have made a long-term commitment to advancing the epidemiology of hypertension. Populations of African descent provide special opportunities for this research, given the range of disease rates seen among these groups with a common genetic ancestry and the high prevalence in the US. In particular, the heritable effects appear to be estimated with more precision in Nigeria where the mix of environmental exposures is less complex. Consistent progress has been made in the technology and analysis required for molecular studies; building on this experience should make it possible to further refine our understanding of the contribution of genes to this important cause of death and disability. ? ?
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