The influence of common gene variants of the xenobiotic receptor (PXR) in genetic susceptibility to intrahepatic cholestasis of pregnancy.
BACKGROUND
The xenobiotic nuclear pregnane X receptor is implicated in many physiological pathways and diseases, including bile acid detoxification and cholestasis. Aim To estimate the contribution of common gene variants of the xenobiotic receptor (pregnane X receptor, PXR) to genetic susceptibility to intrahepatic cholestasis of pregnancy.


METHODS
A total of 101 intrahepatic cholestasis of pregnancy patients and 171 healthy pregnant women in the third trimester of their pregnancies were included. 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, with a minor allele frequency > or =0.10 and representing 33 polymorphic sites were genotyped. Besides these, three additional SNPs (rs3814057, rs6785049, and rs7643645) were included because they showed previous evidence of functionality.


RESULTS
Genotypic test for single SNPs showed that rs2461823 genotypes were significantly associated with intrahepatic cholestasis of pregnancy (P < 0.0069), OR per G allele: 1.44, 95% CI: 1.01-2.05, P < 0.042. The Cochran-Armitage test for trend and the allelic test showed a significant association with disease status (P < 0.04 and 0.03 respectively), G being the risk allele. A positive association between rs2461823 and ALT, AST, and bilirubin concentrations was observed. Neonate birth weight adjusted by the Capurro index was significantly associated with rs2461823 (P < 0.05); the proportion of the total variation attributed to rs2461823 genotypes was 7.8%.


CONCLUSIONS
Common PXR polymorphisms may contribute to the genetic susceptibility to intrahepatic cholestasis of pregnancy.
Castaño
G
G
Research Council in Health, Government of City of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
Burgueño
A
A
Fernández Gianotti
T
T
Pirola
C J
CJ
Sookoian
S
S
D000328:Adult; D000704:Analysis of Variance; D001647:Bile Acids and Salts / Q000378:metabolism; D001724:Birth Weight; D002780:Cholestasis, Intrahepatic / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D005865:Gestational Age; D006706:Homeostasis; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D011263:Pregnancy Trimester, Third; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*; D012621:Seasons; D013020:South America / Q000453:epidemiology; D015262:Xenobiotics
D001647:Bile Acids and Salts; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D015262:Xenobiotics