Genome-to-genome analysis identifies the effect of the host immune systems on Mycobacterium tuberculosis and its impact on clinical outcomes
Background: To date, host genome-wide association studies (GWAS) of tuberculosis (TB) among global populations have provided limited evidence of shared trans-ethnic signals. This observed heterogeneity in GWAS signals may be due to the diverse strains of Mycobacterium tuberculosis (M.tb) in existence.
Materials and Methods: To characterize host-pathogen interplay at the genomic level, we conducted the first genome-to-genome (g2g) analysis of TB to systematically test the interaction between variations in human and M.tb genomes. Using paired human host and M.tb data from 1,632 individuals with a history of active TB, we ran >1.4 billion mixed effects logistic regressions correcting for host population structure and relatedness.
Results: Using this g2g, hypothesis-free approach, (1) we identified three significant human risk loci associations to M.tb variants using a permutation based genome-wide threshold at P = 3.71⨉10-11. The top associated variant is rs3130660 (OR = 1.37 95% CI: 1.32-1.43, P = 3.57⨉10-14), located in the HLA class I region, is an intronic variant of FLOT1. The FLOT1 protein is a membrane-raft associated protein and plays a role in vesicle trafficking and cell morphology. We used data presented in the GTEx portal to search for quantitative trait loci (QTL) signals. We observed a significant expression QTL (eQTL) in the thyroid tissue (P = 1.4⨉10-28) between the top associated variant and FLOT1. We also found strong evidence that the GWAS and eQTL associations share the same leading variant (posterior probability = 0.79), suggesting FLOT1 is likely the causal gene that put selective pressure on the M.tb genome. (2) We identified 80 M.tb variants that are strongly associated with the host genome. These g2g variants are phylogenetic markers for a unique subpopulation of the Beijing strain in Peru, suggesting potential local adaptation of M.tb. (3) We found a strong correlation between the identified subpopulation of the Beijing strain (g2g-Beijing) and clinical outcomes. We found individuals exposed to the g2g-Beijing strains were more likely than those exposed to non-g2g Beijing strains to have incident infection at any time during 12 months of follow-up (Cox frailty proportional hazards model, P = 0.07). We also found that the g2g-Beijing strain is more likely to be drug resistant than other Beijing strains (chi-square, P = 1.9⨉10-5).
Conclusion: Our findings suggest that the human host developed immunity towards a specific subpopulation of the M.tb Beijing strain in Lima, Peru. Consequently, this makes individuals with the presented strain have distinct clinical outcomes.