The nuclear receptor PXR gene variants are associated with liver injury in nonalcoholic fatty liver disease.
OBJECTIVE
To explore the contribution of gene variants and derived haplotypes of the pregnane X receptor (NR1I2) to the severity of nonalcoholic fatty liver disease (NAFLD).


METHODS
A total of 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 single nucleotide polymorphisms (SNPs; rs12488820 C/T, rs2472671 C/T, rs2461823 A/G, and rs1054191 A/G) encompassing 36 kb in chromosome 3 and representing 33 polymorphic sites (r2>0.8) were genotyped. Four additional SNPs (rs3814055, rs3814057, rs6785049, and rs7643645) were also included because they showed earlier evidence of functionality.


RESULTS
Genotypic tests for single SNPs showed that rs7643645 and rs2461823 were significantly associated with disease severity by ordinal multinomial analysis (P<0.0015 and 0.039, respectively). A significant association was also observed under the additive model for both variants (P<0.00038 and 0.012, respectively). Consistent with the analysis of individual markers, we observed that the multimarker composed of rs2461823/A-rs7643645/G was significantly associated with disease severity (P<6.9 x 10(-5), beta: 0.45). In addition, the rs7643645/G variant was significantly associated with ALT level (P<0.026), a surrogate marker of severe liver injury. Finally, in univariate analysis rs7643645/G was significantly associated with fatty liver disease (P<0.04), with an odds ratio of 1.457 (95% confidence interval: 1.018-2.086).


CONCLUSIONS
Our study suggests that pregnane X receptor polymorphisms and related haplotypes may contribute to disease severity in NAFLD by influencing the individual susceptibility to progress to more severe stages of the disease.
Sookoian
Silvia
S
Clinical and Molecular Hepatology Laboratory, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Argentina. ssookoian@lanari.fmed.uba.ar
Castaño
Gustavo O
GO
Burgueño
Adriana L
AL
Gianotti
Tomas Fernández
TF
Rosselli
María Soledad
MS
Pirola
Carlos Jose
CJ
D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000473:pathology; D003430:Cross-Sectional Studies; D005234:Fatty Liver / Q000235:genetics / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*
C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid