The pathogenesis of gallstone disease is complex and a variety of environmental predisposing factors such as obesity and rapid weight loss, nutrition, certain medications and number of pregnancies have been identified [1–6]. However, human and murine data suggest a strong genetic component for the risk of gallstone formation [7–18]. Very recently, Renner et al. have identified SLC10A2 (apical sodium-dependent bile acid transporter; protein name ASBT) as a novel susceptibility gene for cholelithiasis in humans [19]. SLC10A2 encodes the cholangiocyte bile salt transporter protein whose expression is reduced by a lithogenic diet in mice [20] and mediates intestinal bile acid absorption [21, 22]. ASBT is regulated by changes in gene expression in response to biliary bile salt concentration and inflammatory cytokines and is thought to enable cholangiocytes to sense biliary bile salts in order to activate intracellular signaling pathways [23] and to promote cholehepatic shunting of bile salts. Furthermore, ASBT expression in the cholangiocyte apical membrane is regulated by secretin [24]. It has been shown that in gallstone patients, ileal ASBT expression is diminished, and that this is associated with low cytosolic ileal lipid binding protein (ILBP) and basolateral organic solute bile acid exporter (OSTα-OSTβ) expression indicating impaired enterohepatic circulation of bile salts at least in a subset of patients with cholelithiasis [25, 26]. The regulation of ASBT expression also appears weight specific and so far, a diminished ASBT expression has only been shown in non-obese gallstone patients [25, 26].

The recent study by Renner et al. suggested that a single nucleotide polymorphism (SNP) rs9514089 mapping within the SLC10A2 locus is a genetic determinant of gallstone disease, expressing gender and weight specificity with higher risk observed in men and in normal-weight subjects [19]. Since the sample sizes of the two cohorts from Germany included in the recent study were rather small (N = 127 from Stuttgart and N = 368 from Aachen), we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs and performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in the three independent cohorts (Stuttgart, Aachen and Sorbs).

Recently, SLC10A2 was suggested as a novel susceptibility gene for cholelithiasis in humans [19]. The data by Renner et al. indicated that the SNP effects were most pronounced when calculated in the recessive mode of inheritance, i.e. the risk of gallstone development was highest in subjects homozygous for the rs9514089 G allele. Therefore, we performed a meta-analysis including three independent cohorts (previously published cohorts from Stuttgart and Aachen and the cohort of Sorbs) and assuming a recessive mode of inheritance. Although there was no significant difference in minor allele frequencies between the three cohorts the risk allele was the G allele in the Stuttgart and Aachen cohorts but the A allele in the Sorbs. This effect is most likely driven by the small samples sizes in each genotype group in the cohorts. Furthermore, gene-environmental interactions based on factors such as eating behavior and nutrition composition as well as gene-gene interactions should be taken into account. In our study the meta-analysis of all three cohorts did not indicate any significant effect of the rs9514089 genotype on gallstone risk. The Sorbs and the Aachen cohort showed a trend of association in the subgroup of non-obese individuals indicating a possible relationship between the SNP effect and obesity as suggested by Renner et al. [19]. This would be in line with the reported weight specific regulation of the ASBT expression. However, so far, a diminished ASBT expression was confirmed only in non-obese gallstone patients [25, 26]. Also, since effect direction of the rs9514089 variant is different in the Sorbs the meta-analysis did not reveal any significant association in the combined analysis of all three cohorts.

In the Sorbs a nominal association of the SLC10A2 genotype and cholelithiasis was observed in the non-obese subgroup, even though the SNP effect could only be detected in women. This may be due to skewed gender distribution in favor of women and thereby greater statistical power for the female subset. The differences between the populations do not necessarily represent population specific effects of the gene variant. Consistent with the effect in the entire cohort the effect direction also in this subgroup was opposite in the Sorbs compared with the Aachen cohort. This could be attributed to population specific environmental factors or a different phenotype distribution in each population or it could be simply due to the lack of power based on the small samples sizes of the cohorts.

Furthermore, our meta-analysis did not confirm the reported effects of rs9514089 on serum total cholesterol [19]. However, the link between circulating lipid levels and development of gallstones has not been completely elucidated.

The effect of rs9514089 genotype on gallstone risk was not replicated in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism