Sanderson da Silva Coelho, Bárbara Casella Amorim, Jeferson Vidart Ramos, Ana Paula da Costa Marques, Sandra Maria do Valle Leone de Oliveira, Ana Carla Pereira-Latini, Vânia Nieto Brito de Souza, Grazielli Rocha de Rezende Romera, Dayane Alves de Melo, Viviane Lima de Albuquerque, Alessandra Pontillo, Beatriz Aparecida Soares Pereira, Ricardo de Souza Cavalcante, Rinaldo Poncio Mendes, Anamaria Mello Miranda Paniago, Wellington Santos Fava, James Venturini
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.
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.