An exome wide association study of pulmonary tuberculosis patients and their asymptomatic household contacts

Tuberculosis is a leading cause of death in India. To identify genetic variants associated with susceptibility or resistance to Mycobacterium tuberculosis infection, we have performed an exome-wide association study with 0.2 million exonic variants among 119 pairs of tuberculosis patients and their clinically asymptomatic household contacts. The strongest association was identified for rs61104666[A], a synonymous variant (p.E292E) of exon 5 of the gene SIGLEC15 (OR = 2.4, p = 1.49 × 10−5). We also found association of non-coding variants in the 3′UTR region of a gene encoding the class II human leukocyte antigens (HLAs), HLA-DRA. rs13209234[A] (minor allele frequency (MAF) = 13.8%) (OR = 0.35, P = 2.5 × 10−4) and rs3177928[A] (minor allele frequency (MAF) = 13.7%) (OR = 0.35, P = 3.3 × 10−4) were associated with protection from tuberculosis. These two SNPs, rs13209234 and rs3177928, are in complete linkage disequilibrium. These associations remained valid when additional data on freshly recruited individuals were jointly analyzed on 250 patient-control pairs. The identified gene, HLA-DRA, suggest involvement of immune regulation, indicating pathways associated with antigen presentation in tuberculosis infection.