Heterozygote Advantage of the rs3794624 Polymorphism in CYBA for Resistance to Tuberculosis in Two Chinese Populations

Abstract

Phagocyte Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase complex is a key enzyme that catalyzes the production of reactive oxygen species, which mediate oxygen-dependent killing of microorganisms, such as Mycobacterium tuberculosis. P22phox, encoded by CYBA, is the key regulatory subunit of NADPH oxidase. Our study aimed to investigate the association of CYBA polymorphisms with susceptibility to tuberculosis. Three SNPs (rs9932581, rs3794624 and rs4673) were genotyped in the discovery cohort composed of Chinese Han individuals. We found that the A allele of rs3794624 was a significant protective factor against tuberculosis (GA vs. GG: OR = 0.74, 95% CI 0.57-0.96; GA vs. GG+AA: OR = 0.73, 95% CI 0.56-0.95), which was then replicated in the Chinese Tibetan population (GA vs. GG: OR = 0.68, 95% CI 0.51-0.92; AA+GA vs. GG: OR = 0.70, 95% CI 0.52-0.93; GA vs. GG+AA: OR = 0.68, 95% CI 0.51-0.92). Meta-analysis including both cohorts identified overdominance as the best genetic model and provided robust evidence for the protective effect of the rs3794624 GA genotype against tuberculosis without any evidence of heterogeneity (GA vs. GG+AA: OR = 0.71, 95% CI 0.58-0.86). Our study found an association between the GA genotype of rs3794624 in CYBA with decreased tuberculosis susceptibility in two Chinese populations. Further analyses are needed to reveal the potential function of this SNP.