Host susceptibility to blastomycosis: a scoping review and case-control association study

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