Functional Variants of the Central Bile Acid Sensor FXR Identified in Intrahepatic Cholestasis of Pregnancy

Background & Aims: Intrahepatic cholestasis of pregnancy (ICP) is characterized by liver impairment, pruritus, and elevated maternal serum bile acids. It can cause premature delivery and intrauterine death. Bile acid synthesis, metabolism, and transport are regulated by the bile acid sensor FXR, and we hypothesized that genetic variation in FXR confers susceptibility to ICP. Methods: The coding regions and intron/exon boundaries of FXR were sequenced in 92 British ICP cases of mixed ethnicity. Subsequently, a case-control study of allele frequencies of these variants in 2 independent cohorts of Caucasian ICP patients and controls was performed. Variants were cloned into an FXR expression plasmid and tested in functional assays. Results: We identified 4 novel heterozygous FXR variants (−1g>t, M1V, W80R, M173T) in ICP. W80R was not present in Caucasians and M1V was detected uniquely in 1 British case. M173T and −1g>t occur both in Caucasian cases and controls, and we found a significant association of M173T with ICP (OR, 3.2; 95% confidence interval, 1.1–11.2; P = .02) when the allele frequencies of both Caucasian cohorts were analyzed together. We demonstrate functional defects in either translation efficiency or activity for 3 of the 4 variants (−1g>t, M1V, M173T). Conclusions: This is the first report of functional variants in FXR. We propose that these variants may predispose to ICP, and because FXR has a central role in regulating bile and lipid homeostasis they may be associated with other cholestatic and dyslipidemic disorders.

Abbreviations used in this paper: DBD, DNA-binding domain, EcR, ecdysone receptor, FXR, farnesoid X receptor, GGT, γ-glutamyl transpeptidase, ICP, intrahepatic cholestasis of pregnancy, PCR, polymerase chain reaction, SHP, short heterodimer partner, USP, ultraspiracle