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 01.02.2015
• Subjects: Female; Gallstones - genetics; Gastroenterology and Hepatology; Genetic Variation; Humans; Internal Medicine; Male; Polymorphism, Single Nucleotide; Receptors, Cytoplasmic and Nuclear - genetics; Ostα/β; GWAS; single nucleotide polymorphism; base pair; β3-adrenergic receptor; 25-hydroxycholesterol 7-alpha-hydroxylase; organic solute transporters α and β; odds-ratio; fibroblast growth factor; ILBP; HWE; NTCP; ASBT; SHP; ATP-binding cassette sub-family B member 11; matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; RT-qPCR; linkage disequilibrium; FGF; bile acid; body mass index; CYP7B1; apical sodium bile acid transporter; MALDI-TOF MS; ADRB3; SEM; standard error of the mean; BA; FXR; cholesterol 7-alpha-hydroxylase; ABCB4; liver receptor homologue 1; ABCB11; LRH1; CYP7A1; bp; ATP-binding cassette, sub-family B, member 4; SNP; Real-Time Quantitative PCR; ATP-binding cassette proteins G5/G8; Na+-taurocholate cotransporting polypeptide; BMI; OR; farnesoid X receptor; CI; ABCG5/G8; Hardy-Weinberg equilibrium; short heterodimer partner; LD; confidence interval; genome-wide association studies; ileal lipid binding protein
• ISSN: 2210-7401; 2210-741X
• DOI: 10.1016/j.clinre.2014.07.002

Summary Background and aim 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. Methods 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. Results 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). Conclusions 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.