Host susceptibility to blastomycosis: a scoping review and case-control association study
Bibliographic record
Abstract
Blastomycosis is a pulmonary disease caused by Blastomyces dermatitidis, a dimorphic fungus endemic to Manitoba and northwestern Ontario. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2, and VDBP shown to influence susceptibility. However, additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to establish what is known about susceptibility to blastomycosis and explore genetic risk factors in a case-control cohort. We conducted a scoping review to establish current knowledge on blastomycosis immunity and a literature review to identify candidate genes influencing susceptibility to fungal and mycobacterial infections. Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified, and filtered according to best practices. We performed candidate gene prioritization and variant aggregation to identify genetic associations and explored the full exome dataset. The scoping review included 58 articles on susceptibility to blastomycosis. TNF-a, GM-CSF, CD4+ deficiency, and the IL-12-IFN-y pathway had the most evidence as susceptibility factors. The literature review identified 86 candidate genes relevant to fungal and mycobacterial infections. One hundred and three genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single-variant analysis although two non-synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene-based association analysis found TLR1 and GATA2 enriched in controls (p = 0.024 and 0.051, respectively) suggesting a possible protective effect, although GATA2 has previously been associated with blastomycosis susceptibility. Gene cluster analysis identified genetic variants in genes of chromatin remodeling, proteasome, and intraflagellar transport significantly enriched in cases (false discovery rates <14%). Case enrichment of intraflagellar transport genes is interesting as there are previous case reports of blastomycosis and defects in mucociliary function. The findings in this thesis show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to blastomycosis can help to inform clinical practice for improved outcomes.
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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 | 0.008 | 0.035 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.006 |
| Bibliometrics | 0.011 | 0.018 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".