Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans

Background/Aims From quantitative trait locus mapping in inbred mice, we identified the Nr1h4 gene encoding the nuclear bile salt receptor FXR as a candidate gene for the cholesterol gallstone susceptibility locus Lith7. Here, we investigated further an association of the gene encoding FXR and gallstone susceptibility in mice and humans. Methods The Nr1h4 gene was sequenced in inbred mouse strains with susceptible and resistant Lith7 alleles. Quantitative RT-PCR was employed to determine mRNA expression levels. Gallstone carriers and control subjects of three different populations comprising 1004 individuals were genotyped for polymorphisms of the orthologous human gene detected by sequencing. Results Expression and sequence analyses in inbred mice were consistent with Nr1h4 underlying Lith7. In the human populations, we identified three frequent haplotypes that accounted for >95% of all haplotypes observed. In a Mexican population, the most common haplotype NR1H4_1 was associated with gallstone prevalence. In contrast, NR1H4_1 displayed no association with gallstone prevalence in a German population, whereas in a Chilean population we observed a trend towards a protective effect of NR1H4_1. Conclusions Our study in an inbred mouse model and in three ethnically distinct populations indicates complex interactions of NR1H4 alleles and other risk factors for the development of cholelithiasis.