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.

Underwhelming or Misunderstood? Genetic Variability of Pattern Recognition Receptors in Immune Responses and Resistance to Mycobacterium tuberculosis

“…Studies evaluating TLR2 mutations in TB have provided inconsistent results, which limited the interpretation of its role in TB pathogenesis (176,177). Moreover, TLR4 and TLR9 have also been suggested to contribute to TB susceptibility (178)(179)(180).…”

IDUA Gene Variants and Response to Zoledronic Acid Treatment in Chinese Women with Postmenopausal Osteoporosis

“…11 Gene polymorphisms that create, alter, or destroy phosphorylation sites have been recognized as functional variants for human diseases, such as prostate cancer (TP53 rs1042522) 12 and tuberculosis (TLR2 rs5743708). 13 Niu et al found that IDUA phosphorylation-related SNPs rs3755955 and rs6831280 exert indirect effects on nearby phosphorylation sites, which could affect the risk of OP. 6 Wang et al recruited 172 OP patients with lowtraumatic fractures and 156 OP patients without fracture to investigate the relationship of two SNPs (rs3755955 and rs6831280) with BMD and fractures.…”

“… 11 Gene polymorphisms that create, alter, or destroy phosphorylation sites have been recognized as functional variants for human diseases, such as prostate cancer (TP53 rs1042522) 12 and tuberculosis (TLR2 rs5743708). 13 Niu et al found that IDUA phosphorylation-related SNPs rs3755955 and rs6831280 exert indirect effects on nearby phosphorylation sites, which could affect the risk of OP. 6 …”

Polymorphisms in interferon pathway genes and risk of Mycobacterium tuberculosis infection in contacts of tuberculosis cases in Brazil

“…The present study was based on analyses performed retrospectively on a cohort of contacts of pulmonary TB patients, recruited between November 1998 through March 2004. The parent study was reported previously (Cubillos-Angulo et al, 2019). The cases and controls were enrolled in the state of Rio de Janeiro, Brazil where the population is mostly white and brown ('parda, mixed ethnic ancestries) (IBGE, 2012).…”

“…In a longitudinal investigation examining TB contacts from Brazil, we recently found that polymorphisms in toll-like receptor 4 (TLR4) and tumor necrosis factor (TNFA) are associated with increased risk of TST conversion and development of active TB (Cubillos-Angulo et al, 2019). Here we investigated in this same cohort whether genetic variation of Type I IFN pathway genes were associated with susceptibility to Mtb infection by examining single nucleotide polymorphisms (SNPs) involved in DNA and RNA sensing: (rs1101998, rs1633256, rs866484 in IFI16-PYHIN1-AIM2 region, rs59633641 and rs10887959 in IFIT5), rs304478 and rs304498 in IFIT1 and the IFN signaling pathway (rs11246213 [IRF7]).…”