Association of FXR gene variants with cholelithiasis

SummaryBackground and aimImpairment of bile acid homeostasis is the most important risk factor of gallstone disease. Thereby the bile acid sensor farnesoid X receptor (FXR) plays a pivotal role in hepatic and intestinal bile acid metabolism. In this explorative study, the FXR gene was investigated to identify gene variants, associated with gallstone formation in a Caucasian population.MethodsSequencing of the FXR gene was conducted in a randomly selected cohort of gallstone carriers (n = 30) and control subjects (n = 16) from Stuttgart, Germany. Genomic DNA was obtained from blood leukocytes. Genotype frequencies were established in the total cohort (controls: n = 133, gallstone carriers: n = 74). For expression analysis, total RNA and protein were isolated from ileal biopsies.ResultsThe sequencing showed the sole appearance of 10 SNPs in gallstone carriers. Further genotype analysis revealed significant gender- and weight-dependent frequency differences of 3 SNPs between gallstone carriers and controls in males (rs35724: OR = 4.73, P = 0.022) and normal weight subjects (rs11110385: OR = 3.67, P = 0.027; rs11110386: OR = 3.67, P = 0.027) applying the 11 + 12 < > 22 allele model. Furthermore, rs11110385 carriers showed a significantly decreased FXR protein expression (11 + 12 < > 22: P = 0.003). Significant mRNA expression differences between lean rs11110385 carriers and non-carriers were observed in FXR target genes (decrease: ILBP: P = 0.042, OSTalpha: P = 0.071, FGF19: P = 0.011. Increase: LRH1: P = 0.044).ConclusionsThree FXR gene variants (rs35724, rs11110385, rs11110386) were identified as potential susceptibility factors for cholelithiasis in a German cohort in gender- and weight-dependent manners. Thereby the tag SNP rs11110385 seemed to influence the activation of the FXR gene.