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Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients.

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?

SUBMITTER: Wilson A

PROVIDER: S-EPMC7366697 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients.

Wilson Aze A Wang Qian Q Almousa Ahmed A AA Jansen Laura E LE Choi Yun-Hee YH Schwarz Ute I UI Kim Richard B RB

Scientific reports 20200716 1

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 ...[more]

PMID: 32678214

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Project description:The presence of a native collateral circulation in tissues lessens injury in occlusive vascular diseases. However, differences in genetic background cause wide variation in collateral number and diameter in mice, resulting in large variation in protection. Indirect estimates of collateral perfusion suggest that wide variation also exists in humans. Unfortunately, methods used to obtain these estimates are invasive and not widely available. We sought to determine whether differences in genetic background in mice result in variation in branch patterning of the retinal arterial circulation, and whether these differences predict strain-dependent differences in pial collateral extent and severity of ischemic stroke. Retinal patterning metrics, collateral extent, and infarct volume were obtained for 10 strains known to differ widely in collateral extent. Multivariate regression was conducted, and model performance was assessed using K-fold cross-validation. Twenty-one metrics varied with strain (p<0.01). Ten metrics (e.g., bifurcation angle, lacunarity, optimality) predicted collateral number and diameter across seven regression models, with the best model closely predicting (p<0.0001) number (±1.2-3.4 collaterals, K-fold R2=0.83-0.98), diameter (±1.2-1.9 ?m, R2=0.73-0.88), and infarct volume (±5.1 mm3, R2=0.85-0.87). An analogous set of the most predictive metrics, obtained for the middle cerebral artery (MCA) tree in a subset of the above strains, also predicted (p<0.0001) collateral number (±3.3 collaterals, K-fold R2=0.78) and diameter (±1.6 ?m, R2=0.86). Thus, differences in arterial branch patterning in the retina and the MCA trees are specified by genetic background and predict variation in collateral extent and stroke severity. If also true in human, and since genetic variation in cerebral collaterals extends to other tissues at least in mice, a similar "retinal predictor index" could serve as a non- or minimally invasive biomarker for collateral extent in brain and other tissues. This could aid prediction of severity of tissue injury in the event of an occlusive event or development of obstructive disease and in patient stratification for treatment options and clinical studies.

Dataset Information

Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients.

Publications

Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients.

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