A Common NLRC4 Gene Variant Associates With Inflammation and Pulmonary Function in Human Immunodeficiency Virus and Tuberculosis

Background Inflammasomes mediate inflammation in adults living with both human immunodeficiency virus (HIV) and tuberculosis (TB), but the relevance of inflammasome gene polymorphisms in TB-associated pulmonary damage is unknown. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in inflammasome pathway genes modify systemic and pulmonary inflammation, contributing to respiratory impairment in adults living with HIV/pulmonary TB. Methods This was a prospective cohort study set in South Africa following individuals living with HIV/TB up to 48 weeks post-antiretroviral therapy (ART) initiation. Ten functional SNPs in 5 inflammasome pathway genes were related to circulating inflammatory biomarkers and lung function assessed by spirometry pre- and post-ART initiation. Analyses used 2-sided t tests, Wilcoxon rank sum tests, Spearman correlation coefficients, linear regression, and generalized estimating equation models. Results Among 102 patients with baseline samples, the minor allele (T) in NLRC4 rs385076 was independently associated with lower levels of interleukin (IL)-18 and IL-6 before and up to 12 weeks post-ART initiation (Benjamini-Hochberg corrected P values Conclusions A common SNP in the NLRC4 inflammasome may modify TB-associated inflammation in clinically relevant ways. This SNP may identify high-risk groups for lung damage in TB. Inhibition of NLRC4 activity may be an important approach for TB host-directed therapy.