Common Variants in the Pregnane X Receptor Gene may contribute to the Genetic Susceptibility to Intrahepatic Cholestasis of Pregnancy in a South-American Population Sample

CASTAÑO GUSTAVO; BURGUEÑO A,; FERNANDEZ GIANOTTI T; PIROLA CJ; SOOKOIAN S

Boston, USA.

Congreso; The Liver Meeting 2009; 2009

American Association for the Study of Liver Disease

Background: The etiology of intrahepatic cholestasis of pregnancy (ICP) is likely to involve genetic factors. Published evidence about the contribution of either mutations or frequent gene variants to the etiology of ICP has been mainly focused on candidate genes that play a role in biliary transport. While the role of xenobiotic nuclear pregnane X receptor (PXR, NR1I2) in ICP remains scarcely explored, the biological evidence suggests that PXR may also be a candidate gene. In fact, PXR is implicated in many physiological pathways and diseases, including bile acid detoxification and cholestasis. Objective: To explore the contribution of common PXR gene variants to the genetic susceptibility of ICP. Research Design and Methods: 101 ICP patients and 167 healthy pregnant women in the third trimester of their pregnancies were included in this study. Cases and controls were matched on ethnicity (three neighboring countries of Argentina: Peru, Bolivia and Paraguay), area of residence and time of recruitment. Four tag SNPs (rs12488820 C/T; rs2472671 C/T; rs2461823 A/G; rs1054191 A/G) encompassing 36 kb in chr.3, with a minor allele frequency 0.10 and representing 33 polymorphic sites (r2 >0.8) were genotyped. Besides, 3 additional SNPs (rs3814057, rs6785049 and rs7643645) were included because they showed previous evidence about functionality. Results: Genotypic test for single SNPs showed that rs2461823 was significantly associated with ICP (P value<0.0069), allelic OR per G allele 1.45 95 %CI: 1.021-2.06. The Cochran-Armitage test for trend and allelic test also showed significant association with the disease status (P value<0.04 and 0.03, respectively), being G the risk allele. We also observed a positive association between rs2461823 and ALT, AST and total and conjugated bilirubin concentrations. Finally, neonate birth weight was significantly associated with the rs2461823 (P value <0.050); the proportion of the total variation attributed to rs2461823 genotypes was 7.8 %. Conclusion: Our study suggests for the first time that common PXR polymorphisms may contribute to the genetic risk of ICP and suggest its potential role as therapeutic target for the treatment of cholestatic disorders. While further studies are required to replicate our findings in different populations, PXR can be regarded as a candidate gene in the pathogenesis of ICP because previous knowledge about the role of PXR in the hepatic response to toxic stimuli, including bile acids, reinforces the biological plausibility of this association.