A comparative genetic study of tuberculosis and asthma susceptibility /
Bibliographic record
Abstract
The worldwide rates of asthma have been increasing in the past twenty years, coinciding with a decreasing prevalence of tuberculosis in the major asthma endemic regions. The hygiene hypothesis proposes that in countries with better hygiene, reduced exposure to pathogens is responsible for the rising prevalence of allergic diseases. Mycobacterium tuberculosis , the cause of tuberculosis (TB), is thought to be a critical effector of the hygiene hypothesis since it can skew the immune system away from developing into an atopy associated immune profile. Hence, absence of exposure to M. tuberculosis might remove suppression of asthma development. Based on the hygiene hypothesis, we reasoned that genetic factors that predispose to TB should be protective for asthma/atopy and vice versa. Consequently, we tested genetic variants for (1) asthma risk based on known genetic effects in TB susceptibility, and (2) TB risk based on known genetic effects in asthma susceptibility. To identify genetic variants for asthma risk, we tested for nonrandom transmission of genetic variants of the Vitamin D Receptor (VDR) and the Natural Resistance Macrophage Protein 1 (NRAMP1) genes, two known TB susceptibility genes, in an asthma family-based cohort of French Canadian. To identify genetic variants for TB risk, we tested for distribution differences of genetic variants of several asthma associated genes: interleukin 4 (IL-4), IL-4 Receptor A (IL4RA), tumour necrosis factor A (TNFA ), lymphotoxin A (LTA) and VDR in TB cases and non-TB controls recruited in Mexico. Only VDR variants showed a risk modulating effect and where analyzed in more detail in the present thesis. In a North-Eastern Quebec asthma family-based cohort, of the 12 VDR variants tested 6 genetic variants located between intron 2 and 3' UTR we found to be strongly associated with asthma (0.0005 < p < 0.01) under an additive model. Haplotype specific genetic effects were also observed for asthma (0.0004 < p < 0.01). By contrast, no variants of the NRAMP1 gene were observed to be associated with asthma in this French Canadian asthma cohort. In the final set of experiments, I tested asthma associated genes for their impact on risk of TB disease. In a Mexican case-control study, 14 VDR variants tested, we observed 2 genetic variants at the 5' end of the gene to be associated (p < 0.05) with either susceptibility to TB, M. tuberculosis infection or disease progression. No associations were observed between genetic variants of IL4RA, TNFA and LTA, and TB or TB related phenotypes. These findings clearly identified VDR as asthma and TB susceptibility gene. However, since the genetic variants associated with asthma differ from those associated with TB it remains unclear how these variants influence the immune system to promote asthma but not TB, and vice versa. Although TB has been proposed as a suppressing force for asthma, other than VDR, we could not detect any genetic effect of TB susceptibility genes in the asthma study, nor effects of asthma susceptibility genes in the TB study. We interpret these findings as evidence against counter-selection of asthma and TB susceptibility gene variants.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 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".