Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study
Bibliographic record
Abstract
enetic susceptibility to the autoimmune B cell destruction that leads to Type 1 diabetes mellitus (T1D) is a complex trait. 1 In recent years, many T1D associations have been reported, but only three (major histocompatibility complex, insulin, and cytotoxic T lymphocyte associated protein 4) have been confirmed in several independent studies. 2 3 Independent confirmation is essential to eliminate artefacts of publication bias, multiple hypothesis testing, and, in findings of case-control studies, population stratification. 4ottini et al recently found, by a case-control design in two independent populations, a novel association of T1D with a single nucleotide polymorphism (SNP) that caused a R620W aminoacid substitution (dbSNP rs2476601) in the lymphoid protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene. 5PTPN22 encodes LYP, a non-receptor tyrosine phos- phatase involved in lymphocyte function.This paper leaves two potential questions unanswered.Firstly, results of case-control studies are potentially artefacts of population stratification, no matter how well matched are the two groups.Secondly, although Bottini et al show that the T allele encodes a protein unable to bind to its important Csk partner, and postulate this as a very attractive candidate mechanism for the genetic effect, they did not address the question of the haplotype structure of the locus and the possibility that the association is due to linkage disequilibrium (LD) with another variant.Here we present the results of a study that confirms this association in a design impervious to population stratification, and in a preliminary step towards addressing the second question, we define the LD block that encompasses the PTPN22-R620W SNP and present a computationally generated list of potentially functional SNPs within the block.
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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 | 0.001 | 0.008 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.005 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".