A Genomewide Search Finds Major Susceptibility Loci for Gallbladder Disease on Chromosome 1 in Mexican Americans

Abstract

Gallbladder disease (GBD) is one of the major digestive diseases. Its risk factors include age, sex, obesity, type 2 diabetes, and metabolic syndrome (MS). The prevalence of GBD is high in minority populations, such as Native and Mexican Americans. Ethnic differences, familial aggregation of GBD, and the identification of susceptibility loci for gallstone disease by use of animal models suggest genetic influences on GBD. However, the major susceptibility loci for GBD in human populations have not been identified. Using ultrasound-based information on GBD occurrence and a 10-cM gene map, we performed multipoint variance-components analysis to localize susceptibility loci for GBD. Phenotypic and genotypic data from 715 individuals in 39 low-income Mexican American families participating in the San Antonio Family Diabetes/Gallbladder Study were used. Two GBD phenotypes were defined for the analyses: (1) clinical or symptomatic GBD, the cases of cholecystectomies due to stones confirmed by ultrasound, and (2) total GBD, the clinical GBD cases plus the stone carriers newly diagnosed by ultrasound. With use of the National Cholesterol Education Program/Adult Treatment Panel III criteria, five MS risk factors were defined: increased waist circumference, hypertriglyceredemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. The MS risk-factor score (range 0-5) for a given individual was used as a single, composite covariate in the genetic analyses. After accounting for the effects of age, sex, and MS risk-factor score, we found stronger linkage signals for the symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. Other genetic locations (chromosomes 2p, 3q, 4p, 8p, 9p, 10p, and 16q) across the genome exhibited some evidence of linkage (LOD >or=1.2) to symptomatic GBD. Some of these chromosomal regions corresponded with the genetic locations of Lith loci, which influence gallstone formation in mouse models. In conclusion, we found significant evidence of major genetic determinants of symptomatic GBD on chromosome 1p in Mexican Americans.

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

“…Consistent with the results of our study, there is supporting evidence from animal and human genetic studies that the ABCG5/G8 transporter is a true lithogenic risk factor: (1) Wittenburg et al 16 mapped a susceptibility locus for gallstone formation to the murine orthologue of the ABCG5/G8 genes, using quantitative trait locus analysis in experimental crosses of inbred mouse strains, and (2) a recent linkage study of 715 individuals from 39 Mexican American families with gallstones provided suggestive evidence of linkage to gallbladder disease on chromosome 2p21, 40 the site of the ABCG5/G8 genes. Despite increasing evidence from mouse studies for gallstone susceptibility genes, 15 none of the murine Lith loci have yet been confirmed in a human population.…”

“…42 Taken together, these studies demonstrate that an identical set of genes might be critical in the regulation of the gallstone trait across species. Because the defect described by Rosmorduc et al 12 has been named GBD1 (gallbladder disease 1) in the OMIM database (www.ncbi.nlm.nih.gov/entrez/ query.fcgi?dbϭOMIM), and 2 additional loci yet to be cloned (GBD2 and GBD3) have been localized in a recent genomewide scan in Mexican American families, 40 we name the ABCG8 variant identified here GBD4, as approved by the HUGO Gene Nomenclature Committee (01-05-07: www.gene.ucl.ac.uk/nomenclature/). In fact, the significant linkage results for the ABCG8 D19H variant in symptomatic cases only (as defined by history of cholecystectomy) suggest that the variant is linked to the presence of both gallstones and gallbladder disease.…”

P2 Promoter Variants of the Hepatocyte Nuclear Factor 4α Gene Are Associated With Type 2 Diabetes in Mexican Americans

“…Subjects used in this study were participants of the SAFDGS, which consists of extended pedigrees of Mexican-American descent and has been described in detail elsewhere (12,13). Diabetes was defined as a fasting plasma glucose level Ն7.0 mmol/l (126 mg/dl) (14,15) or reported physician-diagnosed diabetes and reported current therapy with either oral antidiabetes agents or insulin.…”

Genome-wide genetic investigation of serological measures of common infections

“…The SAFS combines the San Antonio Family Heart Study (SAFHS) 8 and the San Antonio Family Diabetes Gallbladder Study (SAFDGS). 9,10 The combined study is now focused on the identification of genetic risk factors for many common diseases and their quantitative correlates, beyond the initial respective foci on cardiovascular disease and diabetes. Individuals in the SAFHS were randomly ascertained (without regard for disease status), whereas SAFDGS participants were initially recruited on the basis of a single diabetic proband in each pedigree.…”