We request three years of support to test the hypothesis that one or more of three specific mutations for the lipoprotein lipase (LPL) enzyme promote """"""""dyslipidemia"""""""" and hypertension. In several populations, hypertension has been consistently reported to be associated with """"""""dyslipidemia"""""""" (especially elevated triglycerides and VLDL-cholesterol, and decreased HDL-cholesterol). Numerous studies suggest that genetic factors play an important role in the development of both lipid abnormalities and hypertension. This study offers hope for establishing one specific genetic determinant of both hypertension and lipid abnormalities. Our recent findings suggest the hypothesis to be tested. Among 54 adults over age 40 tested using genomic DNA amplifications, 12 persons carried a specific point mutation for LPL. In this small sample of persons over age 40, mutation carriers had more hypertension (p=.02), low HDL-C (p=.04), high triglycerides (p=.Ol), and high VLDL-C (p=.004). Two pedigrees already shown to carry this same mutation will be expanded to find 33 carriers over age 40 among close and distant cousins providing sufficient sample size to confirm or reject this preliminary finding with confidence. Two other LPL mutations found in two large pedigrees for each mutation will be studied in parallel manner. Among these 6 pedigrees already traced for 5 generations, sequentially sampled persons will be tested for LPL genotype, lipids and blood pressure in order to find 33 carriers over age 40 for each of the three mutations for comparison with noncarriers of the same age group. If this hypothesis is confirmed, it will improve our understanding of genetic mechanisms predisposing to specific types of essential hypertension and lipid disorders. The feasibility of this study is established by our past work. We have used genealogical data to trace and recruit over 90% of invited members of very large and cooperative Utah pedigrees like those identified for this project. Tests for LPL mutations and lipids are already being done by our molecular biology lab and CDC standardized lipid lab for the number of samples per week required. The protocol has been improved by following all recommendations of prior reviewers: (1) Added measures of obesity and body fat; (2) Detailed assessment of diet, exercise, smoking and alcohol; (3) Gender specific analyses; (4) More attention to causes of high triglycerides in noncarriers; (5) Time reduced to 3 years.
