MENDELIAN FACTORS UNDERLYING THE DETERMINATION OF BLOOD PRESSURE AND BODY SIZE

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In humans, excess blood pressure (hypertension) and body size (obesity) are associated with increased cardiovascular risk. The association between hypertension and obesity is well established, however, the pathophysiologic relationship remains poorly understood. Both hypertension and obesity are multifactorial phenotypes whose etiologies clearly involve the effects of major genes and polygenes, as well as the effects of numerous environmental factors. In this project, our basic aim is to identify genetic factors involved in the determination of blood pressure and body size. To accomplish this aim, we will employ two different study designs to identify families for the proposed investigations. The first study design will involve the identification and examination of 500 nuclear families with at least two children from Muscatine, Iowa who are unselected for any phenotype. For each participating parent and child in these families we will determine genotypes for STRP loci at 20 cM intervals throughout the genome. Both sib-pair and multipoint identity-by- descent methods of analysis will be used to identify loci that have measurable effects on blood pressure and body size. Once these loci are identified, we will use measured-genotype and marker-association methods of analysis to estimate the magnitude of their effects on the determination of blood pressure and body size. The second study design will focus on Bedouin families from a tribe in the Negev region in the southern part of Israel. This tribe has been ascertained because there are multiple family members with hypertension and/or obesity. Two hundred affected family members will be typed at STRP loci in an initial grid of 20 cM intervals throughout the genome. The affected-pedigree-member method of linkage analysis will be used to identify genetic loci where affected members are significantly more similar than expected by chance, which is an indication that the marker locus is not segregating independently of hypertension or obesity, but rather is linked to these phenotypes. By focusing on these two well-characterized study populations, and using a carefully selected panel of highly polymorphic markers which spans the genome, we expect to identify some of the genetic factors that maintain blood pressure and body size variation in the population (from analysis of the Muscatine nuclear-family data), and major genetic loci linked to hypertension and obesity (from analysis of the Bedouin tribe).