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Interaction between M. tuberculosis Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB.

ABSTRACT: Tuberculosis (TB) remains a major public health threat globally, especially in sub-Saharan Africa. Both human and Mycobacterium tuberculosis (MTBC) genetic variation affect TB outcomes, but few studies have examined if and how the two genomes interact to affect disease. We hypothesize that long-term coexistence between human genomes and MTBC lineages modulates disease to affect its severity. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which we identified three MTBC lineages, of which one, L4.6-Uganda, is clearly derived and hence recent. We quantified TB severity using the Bandim TBscore and examined the interaction between MTBC lineage and human single-nucleotide polymorphisms (SNPs) genome-wide, in two independent cohorts of TB cases (n = 149 and n = 127). We found a significant interaction between an SNP in PPIAP2 and the Uganda lineage (combined p = 4 × 10^-8). PPIAP2 is a pseudogene that is highly expressed in immune cells. Pathway and eQTL analyses indicated potential roles between coevolving SNPs and cellular replication and metabolism as well as platelet aggregation and coagulation. This finding provides further evidence that host-pathogen interactions affect clinical presentation differently than host and pathogen genetic variation independently, and that human-MTBC coevolution is likely to explain patterns of disease severity.

SUBMITTER: McHenry ML

PROVIDER: S-EPMC8617877 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPulmonary tuberculosis (PTB) is a common infectious disease caused by mycobacterium tuberculosis (MTB) and the present study aims to explore the associations of genetic variants within tyrosine kinases 2 (TYK2) with PTB incidence.MethodsA population-based case control study including 168 smear-positive PTB cases and 251 controls was conducted. Five single nucleotide polymorphisms (SNPs) including rs280520, rs91755, rs2304256, rs12720270, rs280519 located within TYK2 gene were selected and MassARRAY® MALDI-TOF system was employed for genotyping. SPSS 19.0 was adopted for statistical analysis, non-conditional logistic regression was conducted. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed to estimate their contributions to PTB incidence.ResultsIn the overall study population, rs91755 TT and rs280519 AA genotypes were found to be associated with reduced PTB risk (OR = 0.34, 95% CI: 0.16-0.72; OR = 0.38, 95% CI: 0.18-0.79, respectively). After stratification for sex, we found that among the male population, rs91755TG/TT, rs12720270AG/GG and rs280519AG/AA genotypes were associated with reduced PTB risk (OR = 0.41, 95% CI: 0.21-0.80; OR = 0.44, 95% CI: 0.21-0.94; OR = 0.42, 95% CI: 0.21-0.82, respectively). After stratification for age, we found that among those aged <60 years, rs91755TT and rs280519AA genotype were associated with reduced PTB risk (OR = 0.29, 95% CI: 0.09-0.90; OR = 0.34, 95% CI: 0.11-1.08, respectively); while rs2304256AC/AA genotype was associated with increased PTB risk (OR = 2.68, 95% CI: 1.05-6.85). Haplotype analysis revealed that AGAAG and ATCGA (Combined with rs280520, rs91755, rs2304256, rs12720270 and rs280519) were associated with increased (OR = 1.54, 95% CI: 1.01-2.37) and decreased PTB risk (OR = 0.70, 95% CI: 0.52-0.94), respectively.ConclusionsThe genetic variants located within TYK2 including rs91755, rs12720270 and rs280519 were found to be associated with modified PTB risk and the SNPs had potential to be the biomarkers to predict PTB incidence risk.

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Interaction between M. tuberculosis Lineage and Human Genetic Variants Reveals Novel Pathway Associations with Severity of TB.

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