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Increased gallstone risk in humans conferred by common variant of hepatic ATP‐binding cassette transporter for cholesterol
Author(s) -
Grünhage Frank,
Acalovschi Monica,
Tirziu Simona,
Walier Maja,
Wienker Thomas F.,
Ciocan Anca,
Mosteanu Ofelia,
Sauerbruch Tilman,
Lammert Frank
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21847
Subject(s) - single nucleotide polymorphism , gallstones , biology , genetics , cholesterol , candidate gene , allele , medicine , genotype , endocrinology , gene
Genomewide scans of 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. Prospectively, we collected data from 178 white individuals with gallbladder stones or history of cholecystectomy in 84 families and from 70 stone‐free controls, as confirmed by abdominal ultrasound. We performed nonparametric linkage (NPL) analysis of affected sib pairs (ASPs) and association tests of cases and controls. 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 significantly increased in randomly selected cases from the ASP cohort compared to the stone‐free controls (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 gallstone patients carried the heterozygous D19H genotype, compared with 8.6% of controls (OR = 2.954; P = 0.026). Conclusion: The linkage and association studies identified the cholesterol transporter ABCG5/G8 as a genetic determinant of gallstone formation, or LITH gene, in humans. The function of this transporter and the results of 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. (H EPATOLOGY 2007.)