Gallbladder disease (GBD) is one of the major causes of morbidity and mortality in the United States. In populations such as the Mexican Americans, the prevalence of GBD is high, and it often clusters with diseases such as non-insulin dependent diabetes mellitus (NIDDM) and obesity. The etiology of GBD is unclear, but it is believed to be multifactorial in origin involving abnormalities of the hepatobiliary system such as supersaturation of bile with cholesterol, changes in cholesterol nucleation, and hypomotility of the gallbladder. Despite the epidemiological evidence for its association with risk factors such as age, sex (higher in women), obesity, native American ancestry, NIDDM, and cardiovascular disease risk factors, evidence for genetic determination of GBD is very limited. The purpose of this project is to conduct a genetic epidemiologic investigation involving molecular genetic data, GBD phenotypes, and statistical genetic techniques to examine the genetic basis for variation in GBD phenotypes in a set of 32 low-income Mexican American families that is currently under investigation in relation to the genetic determination of NIDDM (San Antonio Family Diabetes Study: SAFADS). The overall objectives of this study are to measure genetic effects on GBD phenotypes, and to identify and localized GBD susceptibility genes.
The specific aims are 1) to define GBD phenotypes such as gallstone disease (presence of gallstones), gallstone number (solitary versus multiple), gallstone diameter, and gallbladder wall thickness using ultrasonography; 2) to perform genetic analysis in order to estimate heritabilities for GBD phenotypes, to detect initial evidence of linkage to GBD susceptibility loci, to refine the initial screening using multipoint linkage analysis, and to detect linkage or association using non-parametric methods. Ultrasound GBD phenotypic data will be collected from 720 individuals distributes across 32 families. The initial genome screening will be based on a subset of SAFADS families involving 444 subjects for whom the 10-15 centiMorgan (cM) genome map based on more than 360 markers is already available. After detecting potential signals for linkage, a high resolution 5 cM gene map to be obtained from a full set of SAFADS families(720 individuals) will be used to precisely localize susceptibility loci influencing GBD phenotypes.
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