Association of FXR gene variants with cholelithiasis

• Published in: Clinics and research in hepatology and gastroenterology Vol. 39; no. 1; pp. 68 - 79
• Main Authors: Hirobe-Jahn, Satoko, Harsch, Simone, Renner, Olga, Richter, Dominique, Müller, Oliver, Stange, Eduard F.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.02.2015
• Subjects: Female; Gallstones - genetics; Gastroenterology and Hepatology; Genetic Variation; Humans; Internal Medicine; Male; Polymorphism, Single Nucleotide; Receptors, Cytoplasmic and Nuclear - genetics; FXR; Ostα/β; GWAS; ABCB4; ABCB11; LRH1; CYP7A1; bp; ILBP; SNP; HWE; NTCP; ASBT; SHP; RT-qPCR; BMI; OR; FGF; CI; CYP7B1; ABCG5/G8; MALDI-TOF MS; ADRB3; LD; SEM; BA; single nucleotide polymorphism; base pair; β3-adrenergic receptor; 25-hydroxycholesterol 7-alpha-hydroxylase; organic solute transporters α and β; odds-ratio; fibroblast growth factor; ATP-binding cassette sub-family B member 11; matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; linkage disequilibrium; bile acid; body mass index; apical sodium bile acid transporter; standard error of the mean; cholesterol 7-alpha-hydroxylase; liver receptor homologue 1; ATP-binding cassette, sub-family B, member 4; Real-Time Quantitative PCR; ATP-binding cassette proteins G5/G8; Na+-taurocholate cotransporting polypeptide; farnesoid X receptor; Hardy-Weinberg equilibrium; short heterodimer partner; confidence interval; genome-wide association studies; ileal lipid binding protein
• ISSN: 2210-7401; 2210-741X; 2210-741X
• DOI: 10.1016/j.clinre.2014.07.002

Impairment 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. Sequencing 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. The 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). Three 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.