A human YEATS4 variant confers resistance to TST and IGRA conversion despite Mycobacterium tuberculosis exposure
Bibliographic record
Abstract
BACKGROUND: Despite sustained exposure to Mycobacterium tuberculosis (Mtb), some individuals-so-called resisters-have persistently negative results for the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs). "Resistance to immune conversion" is the best-known clinical correlate for absence of Mtb transmission and protection from tuberculosis (TB). We investigated the human genetic basis of this phenotype by hypothesizing that resisters living with HIV, a major risk factor for TB, would be enriched in genotypes conferring resistance. METHODS: We enrolled two cohorts of people living with HIV (PWH), consisting of 55 resisters and 100 controls-either positive for TST and IGRA or with a history of TB-from South Africa, and 66 resisters and 57 controls from Haiti, two regions where TB is hyperendemic. All study participants underwent whole-genome sequencing (WGS). We performed a genome-wide association study (GWAS) of the resister phenotype, focusing on a comprehensive set of 320,629 common protein-altering and regulatory variants. RESULTS: ). The frequency of the C allele in the combined sample was 0.11, and all four CC homozygotes in our sample were resisters. Consistently, we found a significant depletion of homozygous carriers of the rs622656-C resistance-associated allele in three cohorts of HIV-negative TB patients from Haiti, Morocco, and the UK Biobank. In silico analysis suggested that the rs622656-C resistance-associated allele increased the translation of the nearby YEATS4 gene by suppressing an upstream open reading frame. YEATS4 has been shown to play a role in innate lymphoid cell differentiation, a leukocyte subset. We confirmed experimentally that the rs622656-C resistance-associated allele increased the activity of the reporter gene in HEK293T cells. CONCLUSIONS: We report a new cluster of variants on chromosome 12q15, overlapping the YEATS4 gene, strongly associated with the resister phenotype in two populations of PWH. Our results contribute to the understanding of the molecular mechanisms that block transmission of Mtb.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".