A Common Polymorphism in the Bile Acid Receptor Farnesoid X Receptor Is Associated with Decreased Hepatic Target Gene Expression
Bibliographic record
Abstract
The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African-, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".