Association of liver X receptors (LXRs) genetic variants to gallbladder cancer susceptibility

Abstract

Liver X receptors (LXRs) α and β are ligand-activated transcription factors belonging to the family of nuclear receptors. LXRs play role in control of lipid homeostasis, glucose metabolism, inflammation, and proliferation. LXRs are expressed in gallbladder cholangiocytes and recent studies have shown that LXR-β (-/-) Mice exhibit an estrogen-dependent gallbladder carcinogenesis. However, there are no studies reported in humans. Therefore, using case-control design in the present study, we have evaluated the associations of LXR-α (rs7120118) and LXR-β (rs35463555 and rs2695121) genetic variants with gallbladder cancer (GBC) susceptibility in 400 cases and 200 controls. Genotypes were determined by TaqMan probes. Statistical analysis was done by SPSS and SNPstats. In silico analysis was performed using Bioinformatics tools (F-SNP, FAST-SNP). LXR-β genotypes (rs35463555) [GA + AA] and (rs2695121) [TC + CC] were associated with risk of GBC [OR = 1.46, p = 0.03; OR = 1.52, p = 0.01, respectively] as compared to healthy controls whereas LXR-α (rs7120118) was not associated with GBC risk. LXR-β haplotype [Ars35463555-Crs2695121] showed statistical significant association with GBC [OR = 5.0, p = 0.03]. On stratification based on gender, LXR-β [GA + AA] and [TC + CC] genotypes were found to be significantly associated in females GBC patients [OR = 1.5, p = 0.04; OR = 1.7, p = 0.005, respectively]. The LXR-β [TC + CC] associated with GBC patients with gallstones [OR; 1.8, p = 0.002]. The genetic risk by LXR-β was not modulated by tobacco consumption or age of onset. In silico analysis using FAST-SNP showed "Low-medium risk" by LXR-β (rs2695121) T > C variation. Our results suggest that LXR-β polymorphisms influence gallbladder cancer susceptibility through estrogen and gallstone-dependent pathways.