Genetic association of missense (rs2919643), intergenic (rs2057178) and a 3’UTR (rs1009170) variant with tuberculosis: A replication study from India

To investigate host genetic susceptibility to tuberculosis (TB), we conducted a replication study focussed on candidate SNPs, previously reported to be associated with TB. We examined nine candidate SNPs and genotyped them in an independent cohort of TB cases and household contacts from West Bengal, India. The association with TB was replicated for rs2919643 (Chr 18), rs2057178 (Chr 11) and rs1009170 (Chr 14). rs2919643-C (p=8.81E-5) was a risk allele and rs2057178-A (p=0.04188) was protective against TB in our population. Association of rs1009170; previously reported by us with TB was also replicated in the new set of samples (p=0.0359). rs2919643 is a missense variant present in linkage disequilibrium with a TB associated synonymous SNP rs61104666. The risk genotype rs2919643-CC was associated with higher levels of plasma RANTES and IL5 in household contacts. rs2919643 is an eQTL for an immunosuppressive gene SIGLEC15 and autophagy related gene EPG5. rs2057178 is an eQTL for a pseudogene and present within weak enhancer marks in the lungs. The genomic locus around this SNP rs1009170 encompasses an active transcription factor peak in CD14⁺ monocytes and also serves as an eQTL for NDUFB1, ATXN3 and SLC24A4. TB cases with rs1009170-TT genotype showed lower expression of plasma RANTES compared to the heterozygote. All three associated SNPs have putative regulatory role in lungs and immune associated cells and organs which may be relevant to TB pathogenesis.