Within the framework of an on-going collaborative study of hypertension in populations of African origin, the applicants propose to extend work on the renin-angiotensin system (RAS). A population-based prevalence survey has been completed in Jamaica and will provide samples for genetic analysis. Ten polymorphisms of the angiotensin-converting enzyme (ACE) will be typed in 1,000 individuals from the hypertension survey. Pointwise analyses of linkage disequilibrium between alleles at these polymorphic sites and phenotypes of interest (serum ACE activity, blood pressure as a continuous trait and hypertension as a dichotomous trait) will be conducted. To narrow the critical interval within the ACE gene which contains molecular variants that contribute to the variance of serum ACE activity and/or blood pressure in this population, additional measured haplotype"""""""" analyses will be carried out. Finally, sequencing will be undertaken in the critical interval of the ACE gene to define the existing genetic variation. Support is requested in this application for laboratory analyses at the Tropical Metabolism Research Unit (TMRU), Kingston, Jamaica. Dr. Colin McKenzie, who will carry out the genotyping, recently completed a DPhil at Oxford University in the Wellcome Trust Centre for Human Genetics. The proposed research is a direct extension of his work at Oxford. An important advantage provided by the Jamaican population is the presence of extensive variation in haplotypes. This diversity allows for the analysis of ancestral recombination events to refine the position of variants which influence ACE levels. Dr. McKenzie will be supported by continued collaboration with Oxford investigators, as well as the PI and statistical geneticists at Loyola. A strong collaborative relationship has been established over the last 5 years between the TMRU and Loyola University Medical School. Three NIH grants have been jointly funded between these groups, and a number of publications have been co-authored. This scientific interchange will be further enhanced by the opportunity for new original research at the TMRU. Substantial work on the genetics of hypertension, with a focus on the RAS, has already been already initiated within this collaborative research project, directed by Dr. Cooper and the group at Loyola. However, Dr. McKenzie's contribution will be unique, and will combine advanced genetic methods with the epidemiologic resources that exist within the parent project. In addition, this work will further aid in the development of research capacity within the Caribbean.
