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

Abstract

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. (HEPATOLOGY 2007;46:793-801.)

Genetic study of FGF19 receptor variants in gallstone disease

“…2 Also, in a study of macrophage/neutrophil-specific gp130 knockout mice, deletion of gp130 significantly decreased release of IL-6 from immune cells and was associated with more severe liver injury of concanavalin A hepatitis. 3 In IL-10-deficient mice, additional deletion of IL-6 or STAT3 resulted in hepatic steatosis and the elevation of serum alanine aminotransferase. 4 Thus, activation of IL-6/gp130/STAT3 signaling plays an important role in protecting against liver injury, whereas IL-30 inhibited interaction of IL-6 with gp130 and decreased IL-6-mediated production of IL-10 in a dose-dependent manner.…”

“…1) but not in controls supports the association of the KLB polymorphism with gallstones. However, nonparametric linkage analysis in affected sibs 3 was negative (P > 0.05). In contrast to the KLB variant, both FGFR4 variants are not associated with gallstones in our cohort (data not shown).…”

“…2 To investigate their relevance for gallstone disease, we genotyped common FGFR4 (rs351855, rs376618) and KLB (rs17618244) variants in a cohort of 239 gallstone patients from 107 families (age range, 24-80 years; 86% women) and 248 stone-free controls (age range, 21-78 years; 93% women); patient characteristics of the incipient cohort were reported in HEPATOLOGY. 3 Table 1 shows that the KLB genotype [AA] is more prevalent in cases than controls. Therefore, we tested for associations between genotypes and gallstone disease using contingency tables (allele frequency difference/positivity, heterozygous/homozygous carriers).…”

“…Therefore, we tested for associations between genotypes and gallstone disease using contingency tables (allele frequency difference/positivity, heterozygous/homozygous carriers). 3 Individuals who are homozygous for the minor allele [A] are at increased risk of developing gallstones (odds ratio, 3.23; 95% confidence interval, 1.32-7.92; P ¼ 0.007) as compared to carriers of genotype [GG]. Departure of the KLB genotype distribution from Hardy-Weinberg equilibrium in cases (exact test, P < 0.001; Supplementary Fig.…”

Transporters in cholelithiasis

“…Further, Katsika et al (2005) explored phenotypic variation among twins through structural equation modelling and reported genetic factors to account for 25 % of the variation. ' Gallstone genes ' are continuously being corroborated in genome-wide association studies (GWAS), in case-control cohorts, and in family studies (Buch et al , 2007(Buch et al , , 2010Gr ü nhage et al, 2007 ;Katsika et al , 2010 ).…”