Genomweite Untersuchung identifiziert den hepatischen Cholesterol Transporter ABCG8 als Suszeptibilitäts-Faktor für das humane Gallensteinleiden

Abstract

Gallstone disease is a common disorder with a prevalence of approximately 20 % in industrialized countries. We performed a genome-wide disease association scan of over 500,000 single nucleotide polymorphisms (SNPs) using 280 cases with early onset gallstone disease and 360 sonographically stone-free controls from Germany. A total of 238 lead SNPs were identified, based upon their marker- and region-specific levels of statistical significance, and were subsequently followed-up in another 1100 symptomatic cases and 850 controls. The original disease association was replicated for only one marker, a SNP (Affymetrix id: A-1791411) in the ABCG8 gene (allelic p = 4.1 × 10⁻⁹). Fine-mapping of the ABCG5/ABCG8 locus, using both haplotype and logistic regression analysis, revealed that nonsynonymous SNP rs11887534 in the ABCG8 gene (encoding a D19H amino acid substitution) was found to represent the major source of gallstone risk at this locus. Its association with gallstone disease was further replicated in another 728 patients from Germany (p = 2.8 × 10⁻⁷) and in 167 patients from Chile (p = 0.02). The overall odds ratio (OR) for D19H carriership, as estimated from all German samples combined, was 2.2 (95 % CI 1.8–2.6). In a post-hoc logistic regression analysis, the genotypic effect was found to be independent of known risk factors such as BMI, age and sex. The association with D19H was strongest (OR = 3.3; 95 % CI: 2.5 – 4.3)) in the subgroup of patients with gallstones that contained cholesterol as a major constituent (> 30 %). The ABCG8 protein forms a heterodimer with ABCG5 that actively transports cholesterol into the bile. Since the His19 allele has been shown before to be associated with lower serum cholesterol levels, it appears likely to exert its gallstone predisposing effect by a more efficient transport of cholesterol into the biliary lumen and, therefore, a higher concentration of cholesterol in the bile.