The genetic-epidemiology of intermediate phenotypes associated with familial hypertension is currently being studied in Utah pedigrees and sibships. Of primary interest are markers for the angiotensinogen locus, which has been linked to hypertension, urinary kallikrein excretion and dyslipidemia. The parent grants of this application are funded to perform sibpair and pedigree linkage of hypertension to intermediate phenotypes, including kallikrein, Na-Li countertransport, nonmodulation of the renin- angiotensin system and salt sensitivity. Serum cholesterol, triglycerides, insulin, and HDL-C are also being measured to investigate the syndrome of familial dyslipidemic hypertension. This syndrome associates dyslipidemia, hyperinsulinemia and obesity to early onset familial hypertension. The abnormal kallikrein and dyslipidemia phenotypes are common in the Utah population, and similar frequencies of dyslipidemia have been described in U.S. and European populations. The angiotensinogen marker is very common and has been linked to hypertension in three different populations (France, Utah, and Japan), suggesting that it will be found in the USSR also. There is also less cultural and dietary heterogeneity in the village of Nochur than in the U.S., providing an ideal population for genetic studies. This foreign collaboration will study kallikrein/renin/aldosterone/angiotensinogen and dyslipidemia/hyperinsulinemia in a unique population in the former U.S.S.R. The settlement of Nochur (approximately 6,000 persons, average age of 31) near the Iranian border has a high prevalence of early onset, severe hypertension, CHD and stroke. There are about 800 nuclear families arising from only a small number of clans. Blood pressures from 2342 persons in this population have already been obtained. The blood pressure distribution is significantly bimodal and 4% (N=l04) of measured persons have a diastolic blood pressure above 110 mmHg and 8% have systolic blood pressure greater than 180 mmHg. 37% are hypertensive by WHO criteria, making Nochur ideal to study candidate genes responsible for the high rates of hypertension.
The specific aims of this application include a case-control study to relate intermediate phenotypes to blood pressure and to test for genetic association of candidate loci to hypertension and measured phenotypes. This will be followed by a family genetic study to look for major genes and environmental interactions. Nuclear families of 100 probands with the highest blood pressures will be selected as the high risk families. These 100 probands will be compared to 100 age- and gender-matched controls. Ml family members from the 100 high risk families will be screened. Medical family histories will be obtained from each nuclear family to join families together into individual clans which will be verified by DNA analysis. Genetic segregation and linkage analyses will test for the presence of major genes for measured phenotypes and hypertension, and results will be compared to the Utah population. DNA, plasma and urine will be frozen. DNA will be sent to Utah for genetic linkage and association analyses with candidate genes already available from the parent grant.
