Identification of a functional SNP in an asthma gene: IL1RL1
Bibliographic record
Abstract
Our aim is to identify causal variants for the IL1RL1 gene previously associated with asthma and related phenotypes as well as perform functional assays to uncover the mechanism underlying its involvement in the disease pathogenesis. IL1RL1 has been shown to be sufficient to induce experimental allergic airway inflammation using transgenic and knockdown mouse models. Its expression has been shown to increase in murine and human asthmatic lungs; the ligand for IL1RL1 is Interleukin-33 ( IL33) . The signaling cascade resulting from the binding of TSLP and IL33 is crucial in eosinophilic inflammation characteristic of asthma. The IL1RL1 gene lies in chromosome 2 in the midst of a cytokine gene cluster with IL1R1 , IL1RL2 , IL18R1 and IL18RAP : all encoding for proteins involved in the immune response characteristic of asthma. The region is in relatively high linkage disequilibrium, thus an excellent candidate for narrowing down the asthma association signal to one or more causal SNPs. Firstly, a putative causal SNP is identified based on previous association data, or linkage disequilibrium with associated SNPs, conservation scores and putative binding of regulatory proteins. DNA samples from asthmatics and controls are then genotyped for the candidate SNP using Taqman technology in order to relate genotypes to potential alteration of gene expression. Gene expression assays will be performed to compare levels of expression between the different genotypes as well as between the two SNP alleles. These real time-polymerase chain reaction (RT-PCR) experiments will be conducted for both IL1RL1 isoforms in order to also assess their differential expression depending on our candidate SNP genotype. If changes in expression are observed, we will perform electrophoretic mobility shift assays in order to test if the differential expression is due to the differential binding of a regulatory protein depending on the SNP allele. In order to further confirm that the SNP site is in an important region for gene expression regulation we will perform formaldehyde-assisted isolation of regulatory elements (FAIRE); a method which discriminates between DNA sequences depending on the presence or lack of nucleosome structures. The absence of nucleosome indicates that the region is active and accessible to regulatory elements and thus important for gene regulation.
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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 | 0.001 | 0.001 |
| 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".