The hepatic cholesterol transporter gene ABCG8 confers increased gallstone risk in humans: combined affected sib pair and association study

Introduction: Genome-wide scans in inbred strains of mice have linked the genes encoding the hepatocanalicular cholesterol transporter ABCG5/G8 to gallstone formation. Five nonsynonymous coding single nucleotide polymorphisms (SNPs) in the orthologous human genes are associated with differences in serum cholesterol and plant sterol levels. We now tested these ABCG5/G8 SNPs for linkage and association with gallstone susceptibility in humans.

Methods: We collected 178 Caucasian affected siblings with gallbladder stones or past history of cholecystectomy and 70 stone-free controls, as confirmed by abdominal ultrasound. We performed non-parametric linkage (NPL) analysis in affected sib pairs (ASPs) and association tests in cases and controls.

Results: In ASPs, gallstones were strongly linked to the D19H variant of the ABCG8 gene (NPL score=7.1; P=4.6×10–13). The risk of gallstones in carriers of the 19H allele was also significantly increased in randomly selected cases from the ASP cohort as compared to stone-free controls (odds ratio [OR]=3.018; P=0.017). Consistent with the mouse model, heterozygosity for the lithogenic ABCG8 allele was associated with gallstones in humans; 21.4% of our gallstone patients carried the heterozygous D19H genotype, as compared to 8.6% of controls (OR=2.954; P=0.026).

Conclusions: The linkage and association studies identify the cholesterol transporter ABCG5/G8 as determinant (LITH gene) of gallstone formation in humans. The function of this transporter and the genetic study taken together indicate that in gallstone-susceptible carriers of the ABCG8 19H allele, cholesterol cholelithiasis is secondary to increased hepatobiliary cholesterol secretion