Common Variants in the Pregnane X Receptor Gene may contribute to the Genetic Susceptibility to Nonalcoholic Fatty Liver Disease

SOOKOIAN S; CASTANO GO; BURGUEÑO A,; FERNADEZ GIANNOTTI T; ROSSELLI MS; PIROLA CJ

Honolulu, Hawaii, USA

Congreso; 59 Annual Meeting of The American Society of Human Genetics (ASHG),; 2009

American Society of Human Genetics

Background: Nonalcoholic fatty liver disease (NAFLD), a disease characterized by fat accumulation in the liver, is an emerging epidemic disease affecting 10 to 40 percent of the general population in Western countries, and up to 80% of obese and diabetic individuals. While it is well known that environmental risk factors influence the development and progression of NAFLD, the contribution of the individual genetic variation to disease predisposition is still uncertain. Pregnane X receptor (PXR) is a member of the nuclear receptor superfamily, whose primary function is the regulation of an entire network of genes involved in the detoxification and elimination of xenobiotics from the body. Emerging evidence has also pointed to an equally important role of PXR as an endobiotic receptor by impacting on lipid homeostasis. Objective: To explore the contribution of gene variants and derived haplotypes of the PXR to the histological severity of NAFLD. Methods: 290 individuals were evaluated in a case-control association study, including 188 NAFLD patients with different stages of disease severity and 102 healthy individuals. Four tag SNPs (rs12488820 C/T; rs2472671 C/T; rs2461823 A/G; rs1054191 A/G) encompassing 36 kb in chr.3 and representing 33 polymorphic sites (r2 >0.8) were genotyped. Besides, 4 additional SNPs (rs3814055, rs3814057, rs6785049 and rs7643645) were included because they showed previous evidence about functionality. Results: Genotypic tests for single SNP showed that rs7643645 and rs2461823 were significantly associated with disease severity by ordinal multinomial analysis (p=0.0011 and 0.038, respectively). A significant association was also observed under the additive model for both variants (p=0.00037 and 0.011, respectively). Consistent with the analysis of individual markers, we observed that the multimarker composed by the rs2461823/A-rs7643645/G was significantly associated with the disease severity (p=6.8X10-5, beta 0.45). In addition, the rs7643645/G variant was significantly associated with ALT level (p=0.025), a surrogate marker of severe liver injury. Finally, in univariate analysis the rs7643645/G was significantly associated with fatty liver disease (p value=0.039), odds ratio, 1.457; 95% confidence interval, 1.018-2.086. Conclusion: Our study suggests that PXR polymorphisms and related haplotypes may contribute to the disease severity in NAFLD by influencing the individual susceptibility to progress to more severe stages of the disease.