Seronegative and spondyloarthopathies oral abstracts
Bibliographic record
Abstract
Background: Genome-wide association studies have revealed the polygenic nature of AS. More than 60 genetic influences have been identified, but most of these are non-coding sequences. Protection against AS is afforded by a loss of functional mutation in the cytoplasmic tail of the IL-23 receptor (IL-23R), but there is also a second independent association in this region. This study explores the functional basis for the latter association between AS and single nucleotide polymorphisms (SNPs) in the IL23R-IL12RB2 intergenic region. Methods: We performed conditional analysis on genetic association data at IL23R and used epigenetic data on chromatin remodelling and transcription factor (TF) binding to identify the primary AS-associated SNP. Functional effects were tested in luciferase reporter assays in HEK293T cells and allele-specific TF binding was investigated by electrophoretic mobility gel shift assays. The involvement of candidate TFs in DNA binding was investigated by antibodies in these experiments. We measured mRNA expression levels of nearby genes in CD4 T cells and compared these between cases homozygous for the risk A allele and the protective G allele. The proportions of IL-17A and IFN-g CD4 T cells were measured by FACS and also correlated to patient genotype. Results: Conditional analysis identified rs11209032 as the primary causal SNP within a putative enhancer between IL23R and IL12RB2. Reduced luciferase activity was seen for the risk A allele (P < 0.001) and reduced H3K4me1 methylation was observed in CD4 T cells from 'A/A' homozygotes (P 0.02). Nuclear extract binding to the risk A allele was decreased $3.5-fold compared with the protective allele (P < 0.001). Reduced nuclear factor binding was observed when antibody to TWIST1 was included. The proportion of IFN-g CD4 T cells was increased in A/A homozygotes (P 0.004), but neither IL23R nor IL12RB2 mRNA was affected. Conclusion: The rs11209032 SNP downstream of IL23R forms part of an enhancer allelic variation that may influence Th1 cell numbers. Homozygotes for the risk A allele have more IFN-g-secreting (Th1) cells compared with those with the protective G allele. Further work is necessary to explain how TWIST1 contributes to these important observations.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 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) | 0.000 | 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".