Polymorphisms in TLR4 and TNFA and Risk of Mycobacterium tuberculosis Infection and Development of Active Disease in Contacts of Tuberculosis Cases in Brazil: A Prospective Cohort Study

Abstract

Background: The role of genetic polymorphisms in latent tuberculosis (TB) infection and progression to active TB is not fully understood.

Methods: We tested the single-nucleotide polymorphisms (SNPs) rs5743708 (TLR2), rs4986791 (TLR4), rs361525 (TNFA), rs2430561 (IFNG) rs1143627 (IL1B) as risk factors for tuberculin skin test (TST) conversion or development of active TB in contacts of active TB cases. Contacts of microbiologically confirmed pulmonary TB cases were initially screened for longitudinal evaluation up to 24 months, with clinical examination and serial TST, between 1998 and 2004 at a referral center in Brazil. Data and biospecimens were collected from 526 individuals who were contacts of 177 active TB index cases. TST conversion was defined as induration ≥5 mm after a negative TST result (0 mm) at baseline or month 4 visit. Independent associations were tested using logistic regression models.

Results: Among the 526 contacts, 60 had TST conversion and 44 developed active TB during follow-up. Multivariable regression analysis demonstrated that male sex (odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1-4.6), as well as SNPs in TLR4 genes (OR: 62.8, 95% CI: 7.5-525.3) and TNFA (OR: 4.2, 95% CI: 1.9-9.5) were independently associated with TST conversion. Moreover, a positive TST at baseline (OR: 4.7, 95% CI: 2.3-9.7) and SNPs in TLR4 (OR: 6.5, 95% CI: 1.1-36.7) and TNFA (OR: 12.4, 95% CI:5.1-30.1) were independently associated with incident TB.

Conclusions: SNPs in TLR4 and TNFA predicted both TST conversion and active TB among contacts of TB cases in Brazil.

Keywords: Mycobacterium tuberculosis; Toll-like receptor; single-nucleotide polymorphism; tuberculin skin test; tumor necrosis factor.

Figure 1.

Study flow chart. Index case: first tuberculosis case identified in the household. ^aMissing 2nd TST: 135 cases; ^bMissing 3rd TST: 33 cases and 26 people who missed the 2nd TST showed up. Abbreviation: TST, tuberculin skin test.

Figure 2.

Factors associated with TST conversion. A, Multivariable regression model of variables shown in Tables 3 and 4, which displayed univariate P-value ≤ .2. B, Bayesian network with bootstrap (100×) was used to illustrate the statistically significant associations between the parameters and the presence of TST conversion in the study population. Lines represent direct associations. Associations that remained statistically significant on ≥20 of 100 bootstraps are plotted. Numbers of times each association persisted during bootstrap are shown. Bold lines highlight the strongest associations. All parameters from Table 3 were included. Only those displaying significant associations are shown. Abbreviation: TST, tuberculin skin test.

Figure 3.

Variables associated with development of active TB among contacts of pulmonary TB. A, Multivariable regression model of variables shown in Tables 5 and 6 which displayed univariate P-value ≤ .2. B, Bayesian network with bootstrap (100×) was used to illustrate the statistically significant associations between the parameters and the occurrence of incident TB in the study population. Lines represent direct associations. Associations that remained statistically significant on ≥20 of 100 bootstraps are plotted. Numbers of times each association persisted during bootstrap are shown. Bold lines highlight the strongest associations. All parameters from Table 5 were included. Only those displaying significant associations are shown. Abbreviation: TB, tuberculosis.