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Background  Cholelithiasis is a multifactorial process and several mechanisms of gallstone formation have been postulated. As one of these mechanisms, a decreased expression of the ileal apical sodium-dependent bile acid transporter gene  SLC10A2  in gallstone carriers was described previously. In this study the  SLC10A2  gene was investigated to identify novel genetic variants and their association with gallstone formation.    Methodology/Principal Findings  Study subjects were selected with the presence or absence of gallstones confirmed by ultrasound and medical history. Genomic DNA was obtained from blood leukocytes. Sequence analysis was performed of all six exonic and flanking regions as well as of 2,400 base pairs of the  SLC10A2  promoter in a cohort of gallstone carriers and control subjects from Stuttgart, Germany. Genotype frequencies of newly identified genetic variants (n = 6) and known single nucleotide polymorphisms (n = 24) were established using MALDI-TOF mass spectrometry. Six new genetic variants were found within the  SLC10A2  gene. Although none of the variants was linked to gallstone disease in the Stuttgart cohort overall, the minor allele of SNP  rs9514089  was more prevalent in male non-obese gallstone carriers ( p  = 0.06680, OR = 11.00). In a separate population from Aachen, Germany, the occurrence of  rs9514089  was two-fold higher in gallstone patients (22%) than in corresponding controls (11%) ( p  = 0.00995, OR = 2.19). In the pooled Aachen/Stuttgart cohort  rs9514089  was highly significantly linked to cholelithiasis ( p  = 0.00767, OR = 2.04). A more frequent occurrence was observed for male gallstone carriers (22%) compared to controls (9%) ( p  = 0.01017, OR = 2.99), for the total normal weight group ( p  = 0.00754, OR = 2.90), and for male non-obese gallstone patients ( p  = 0.01410, OR = 6.85). Moreover, for the minor allele of  rs9514089  an association with low plasma cholesterol levels was found especially in gallstone carriers ( p  = 0.05).    Conclusions/Significance  We have identified  SLC10A2  as a novel susceptibility gene for cholelithiasis in humans. Comprehensive statistical analysis provides strong evidence that  rs9514089  is a genetic determinant especially in male non-obese gallstone carriers. The minor allele of  rs9514089  is related to differences in plasma cholesterol levels among the subjects.

A Variant of the SLC10A2 Gene Encoding the Apical Sodium-Dependent Bile Acid Transporter Is a Risk Factor for Gallstone Disease