Abstract
The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G > T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n = 542) was conducted in a Canadian cohort of CD patients. Genotypic analysis (FXR-1G > T, MDR1 3435C > T and PXR -25385C > T) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR = 3.34, 95% CI = 1.58–7.05, p = 0.002) and earlier progression to surgery (hazard ratio, HR = 3.00, 95% CI = 1.86–4.83, p < 0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR = 14.87 95% CI = 4.22–52.38, p < 0.0001) and early progression to surgery (HR = 6.28, 95% CI = 3.62–10.90, p < 0.0001). Women carriers of FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype (p < 0.0001). In HepG2 cells cotransfected with estrogen receptor (ER) and FXR, presence of estradiol further attenuated variant FXR activity. MDR1 and PXR genotypes were not associated with surgical risk. Unlike MDR1 and PXR, FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.
Highlights
Crohn’s disease (CD) is an immune-mediated inflammatory bowel disease defined by remitting and relapsing episodes of intestinal inflammation[1]
Subject selection for all participants, as well as baseline characteristics of CD patients, are presented in Supplementary Figure 1 and Table 1. 1,005 patients referred to the London Health Sciences Centre Personalized Medicine Clinic for disease-specific pharmacogenomic testing were screened for inclusion
To better elucidate a potential molecular basis for the observed effect of farnesoid X receptor (FXR)-1G > T genotype on CD prognosis in female CD patients, we explored a connection between the estrogen receptor-mediated pathway and genetic variation in FXR
Summary
Crohn’s disease (CD) is an immune-mediated inflammatory bowel disease defined by remitting and relapsing episodes of intestinal inflammation[1]. Many studies have attempted to link genetic variation in key genes associated with inflammation, xenobiotic metabolism and transport as well as gene regulators of such pathways to CD susceptibility. Complete FXR deficiency, while rare, does exist in the human population, and has been shown to result in progressive familial intrahepatic cholestasis (PFIC), associated with coagulopathy, jaundice and a rapid progression to liver failure[21,22]. Such data suggest major loss of function mutations in FXR as contributors to CD are unlikely; partial loss of function or expression of FXR may contribute to CD progression or severity. The role of the FXR-1G > T SNV has only been evaluated in a CD population in a very limited capacity[11]
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