THE NUCLEAR RECEPTOR PXR GENE VARIANTS ARE ASSOCIATED WITH LIVER INJURY IN nonalcoholic fatty liver disease

SOOKOIAN S; CASTANO GO; BURGUEÑO A,; FERNANDEZ GIANOTTI T; ROSSELLI MS; PIROLA CJ

The New England University, Biddeford, USA.

Conferencia; Gordon Research Conference; 2009

Gordon Research Organization

Objective: To explore the contribution of gene variants and derived haplotypes of the pregnane X receptor (PXR, NR1I2) to the severity of nonalcoholic fatty liver disease (NAFLD).To explore the contribution of gene variants and derived haplotypes of the pregnane X receptor (PXR, NR1I2) to the severity of nonalcoholic fatty liver disease (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.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.