Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium
Bibliographic record
Abstract
The human major histocompatibility complex (MHC) class II region is associated with genetic susceptibility to multiple sclerosis (MS). Roles for HLA class I loci have been supported in several case-control studies, but this methodology does not consider the known linkage disequilibrium (LD) between class I and II loci. In 1258 individuals from 294 MS families, we analysed class I and II interactions. Using transmission disequilibrium test and haplotype analyses, we found positive associations between MS and several HLA-DRB1*15-HLA-A haplotypes including HLA-DRB1*15-HLA-A*02 (P = 2.41 x 10(-5)) and -HLA-A*03 (P = 8.42 x 10(-6)) and several HLA-DRB1*15-HLA-B haplotypes including HLA-DRB1*15-HLA-B*07 (P = 2.23 x 10(-10)). HLA-DRB1*15 haplotypes divergent for reported HLA-A allelic associations were equally over-transmitted, illustrating no detectable effect of HLA-A or -B alleles in cis on susceptibility. HLA-A and -B alleles on haplotypes not bearing HLA-DRB1*15 were not over-transmitted. Similarly, general over-transmission of HLA-DRB1*15 haplotypes was independent of the HLA-B allele present. Furthermore, HLA-B*07 haplotypes from HLA-DRB1*X-HLA-B*X/HLA-DRB1*X-HLA-B*07 heterozygous parents were transmitted per random expectation giving no indication of HLA-B independence or trans complementation of HLA-DRB1*15 by HLA-DRB1*X-HLA-B*07 haplotypes. These results imply that many reports of class I allelic associations in MS are class II dependent, secondary to LD with class II loci. The lack of independent class I associations suggests that virus-related class I-antigen complexes are not T-cell targets in MS. The inability to replicate confirmed case-control associations highlights the importance of family-based analyses. The frequency of allelic associations not being replicated emphasizes the requirement for constructing multi-locus haplotypes in dissecting associations in regions of tight LD.
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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 | 0.005 | 0.016 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".