Epistatic Interactions Among Inflammasome Gene Variants Are Associated With Reduced Risk of Paracoccidioidomycosis

BACKGROUND: Paracoccidioidomycosis (PCM) is an endemic systemic mycosis in Latin America with marked clinical heterogeneity, suggesting a role for host immunogenetic factors. The NLRP3 inflammasome and IL-1β signaling are important in antifungal immunity, but human genetic evidence remains limited. We evaluated whether single-nucleotide variants (SNVs) in inflammasome-related genes (NLRP1, NLRP3, CARD8, CASP1, and IL1B) are associated with PCM susceptibility, clinical form, and disease severity, including gene-gene interactions. METHODS: We conducted a case-control study including 346 individuals (154 PCM patients and 192 gp43-reactive healthy controls). Genetic associations were tested under multiple inheritance models using logistic regression adjusted for age, sex, smoking, and alcoholism. Epistatic interactions were assessed within the inflammasome-IL-1β axis, with Firth penalized logistic regression as a sensitivity analysis. RESULTS: No single-SNV association with PCM susceptibility, clinical form, or severity remained significant after multiple-testing correction. Pairwise epistasis analysis identified an interaction between NLRP3 rs10754558 and IL1B rs1143634 associated with reduced PCM susceptibility (OR = 0.34; 95% CI: 0.17-0.69; pFDR = 0.015), supported by Firth regression. No significant epistatic interactions were found for clinical form or severity. CONCLUSIONS: Genetic interactions within the inflammasome-IL-1β axis may contribute to PCM susceptibility. The interaction between NLRP3 rs10754558 and IL1B rs1143634 warrants validation in larger, independent cohorts.