A lithogenic variant in the gene that encodes the hepatobiliary transporter ABCG8 has been identified as a risk factor for gallstone disease; this variant has been associated with altered cholesterol excretion and metabolism.
To test the hypothesis that ABCG8 (adenosine triphosphate-binding cassette transporter G8) Asp19His (D19H) genotype predicted risk of gallstones and biliary cancer in the general population, we studied 62,279 white individuals from The Copenhagen City Heart Study and The Copenhagen General Population Study, randomly selected to reflect the adult Danish population aged 20 to 80+ years.
Our findings suggest that ABCG8rs11887534, identified as a gallstone risk single-nucleotide polymorphism by whole genome scan, is also associated with an increased risk of biliary tract cancer.
Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men.
In our study we investigated the contribution of heterozygosity for common variations considered either potentially pathogenic or susceptibility alleles for cholesterol cholelithiasis in adults (c.523A>G (p.Thr175Ala) and c.1954A>G (p.Arg652Gly) in ABCB4, c.1331T>C (p.Val444Ala) in ABCB11 and c.55 G>C (p.Asp19His) in ABCG8) to the aetiology of paediatric idiopathic gallstone disease.
Various polymorphisms (A632V, T400K, D19H, M429V, and C54Y) in the ABCG8 and ABCG5 (Q604E) gene have been found to be associated with several facets of cholesterol metabolism, including baseline cholesterol level, cholesterol kinetics, individual responsiveness of plasma cholesterol to dietary and pharmaceutical interventions for hypercholesterolemia, and increased risk of gallstones.
Recently a large twin study confirmed a genetic predisposition to gallstones and a genome-wide association scan identified the hepatocanalicular cholesterol transporter ABCG8 as the common susceptibility factor for gallstone disease.
Consistent with the mouse model, heterozygosity for the lithogenic ABCG8 allele was associated with gallstones in humans; 21.4% of gallstone patients carried the heterozygous D19H genotype, compared with 8.6% of controls (OR = 2.954; P = 0.026).
Male carriers of the less frequent K allele of ABCG8T400K had a 2.31-fold elevated risk [95% confidence interval (CI) 1.12 approximately 4.76, P=0.023] for gallstone disease compared to male with the common genotype after the adjustment for age, body mass index.