Enrichment of Genetic Variants in the Glucocorticoid Receptor Signalling Pathway in Autoimmune Hepatitis with Failure of Standard Treatment
Bibliographic record
Abstract
The standard treatment for autoimmune hepatitis (AIH) is predniso(lo)ne for remission induction, tapered and followed by azathioprine, which effectively controls the disease in the majority of patients. However, some patients prove to be unresponsive or non-tolerant and require alternative immunosuppressive regimens for disease control. We aimed to investigate whether these AIH patients who experience failure of standard treatment have a genomic basis for their problem in the form of pharmacogenetic variants. Fifty-six consecutive patients with AIH [41 female and 15 male; median age 42 years (12-76)] were retrospectively stratified according to being responders to standard therapy (n = 33) or patients with failure of standard therapy (n = 23). Their blood DNA was exome-captured and sequenced. Genomic variants were filtered and compared between the groups using Ingenuity Variant Analysis (3.1.20150407). The exome sequencing and data processing revealed glucocorticoid receptor signalling to be the most prominently affected pathway among the patients with failure of standard therapy (highly significant). Standard treatment failure was not associated with thiopurine S-methyltransferase variants or the HLA-DRB1*03 genotype. In conclusion, enrichment of variants related to glucocorticoid receptor signalling was a particular genomic trait of the AIH patients in whom standard treatment failed and alternative immunosuppression was required. If confirmed, a future application of this finding may be to identify prospective cases of failure of standard treatment already at diagnosis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 teacher head, 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".