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Epistatic Interactions Among Inflammasome Gene Variants Are Associated with Reduced Risk of Paracoccidioidomycosis
Sanderson da Silva Coelho1, Bárbara Casella Amorim1, Jeferson Vidart Ramos2
1School of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
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.