Genetic and structural interpretation of NLRP1 FIIND domain variants in glioma in an Indian cohort: a pilot study

In an Indian glioma cohort study, researchers examined the genetic and structural implications of NLRP1 FIIND domain variants. Gliomas, particularly glioblastoma, are aggressive brain tumors linked to dysregulated NLR signaling. NLRP1 plays a crucial role in triggering proinflammatory cytokine release and pyroptotic cell death via autoproteolytic cleavage.

The study focused on five NLRP1 polymorphisms, including the missense variant rs11651270 (M1184V) and its impact on the cleavage process. Genetic association models were used to analyze five SNPs (rs371579423, rs58604457, rs57636751, rs11651270, and rs2301583) in glioma patients compared to controls from the GenomeIndia dataset.

Molecular dynamics simulations were performed to evaluate the structural effects of the rs11651270 variant during pre- and post-cleavage states. The rs58604457 (G>A) and rs57636751 (C>T) variants showed strong linkage disequilibrium (r2=1.00) and were significantly associated with a lower odds of glioma (odds ratio ~0.5). The rs11651270 (T>C) variant showed no association with glioma risk.

Interestingly, the rs2301583 variant had a higher frequency in glioma cases, despite being absent from the GenomeIndia control catalogue. Molecular dynamics simulations revealed that the M1184V substitution stabilized the local FIIND architecture by preserving beta-strand organization through persistent interactions with neighboring residues.

This pilot study is the first to integrate genetic and structural analysis of NLRP1 FIIND-domain variants in an Indian glioma cohort, demonstrating the potential benefits of merging population-based genetic association with structural modeling to generate hypotheses and uncover functional mechanisms of inflammasome-gene variants in neuro-oncology.