A214 GENETIC VARIATION IN THE FARNESOID X RECEPTOR PREDICTS CROHN’S DISEASE SEVERITY IN FEMALE PATIENTS
Bibliographic record
Abstract
Abstract Background Crohn’s disease (CD) is an immune-mediated inflammatory bowel disease defined by episodes of intestinal inflammation. There is now an increasing appreciation of the bile acid-sensing nuclear receptor, FXR, as an important regulator of intestinal inflammation, intestinal permeability and response to bacterial overgrowth. Many of these processes are dysregulated in CD. It is unclear how genetic variation in FXR impacts on CD severity. FXR deficiency is rare. Loss of function mutations in FXR as contributors to CD are unlikely; however, partial loss of function of FXR may contribute to CD progression or severity. Our group demonstrated that FXR-1G>T, a SNV adjacent to the ATG start codon, is linked to reduced transactivation of FXR gene targets. We hypothesized that changes in the intestinal barrier as a result of reduced FXR expression among those who harbor the FXR-1T allele are more likely to exhibit a severe CD phenotype compared to G (reference) allele carriers, and thereby experience a more rapid progression to surgery. Alterations in FXR activity may in part be secondary to genetic variation in the FXR gene. Aims To evaluate FXR-1G>T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. Methods A retrospective study (n=542) was conducted in a Canadian cohort of CD patients. Blood samples were obtained for genotypic analysis (FXR-1G>T), as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19. Primary outcomes included risk and time to first CD-related surgery. To better elucidate a potential molecular basis for the observed effect of FXR-1G>T genotype on CD prognosis (more frequent and early surgery) in female CD patients, we explored a connection between the estrogen receptor (ER)-mediated pathway and genetic variation in FXR using a cell-based model. . Results 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 early 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). Furthermore, women carriers of FXR-1GT polymorphism had a nearly three-fold lower FGF19 plasma concentration compared to women with wildtype FXR-1GG genotype (p<0.0001). In HepG2 cells cotransfected with estrogen receptors (ERα and β) and FXR, presence of estradiol further attenuated variant FXR activity. Conclusions FXR-1GT is deleterious to women with CD through ER-mediated attenuation of FXR activation. Female CD FXR-1GT carriers should be considered for more aggressive medical management. Funding Agencies CAG, CCC, CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".