Dataset Information

Association of the TLR1 variant rs5743557 with susceptibility to tuberculosis.

ABSTRACT: Background:Toll-like receptor 1 (TLR1) and TLR6 play important roles in the innate immune response against Mycobacterium tuberculosis (M.TB) via interactions with TIR domain-containing adaptor protein (TIRAP) and myeloid differentiation primary response 88 (MYD88). The aim of this study was to investigate the relationship of TLR1, TLR6, MYD88 and TIRAP polymorphisms with susceptibility to latent tuberculosis infection (LTBI) and tuberculosis (TB). Methods:In total, 204 uninfected healthy controls (HC), 201 individuals with LTBI and 209 TB patients were enrolled. Two interferon-? release assays were used to differentiate individuals with LTBI from uninfected controls. TagSNPs of the four genes were genotyped by the SNPscanTM Kit. The Haploview 4.2 and SHEsis software packages were combined to perform linkage disequilibrium (LD) and haplotype analyses. Multifactor dimensionality reduction (MDR) software was used to investigate gene-gene interaction. The Stata 12.0 software was used to perform meta-analysis of the relationship between rs5743557 and TB susceptibility. Results:The AA genotype of rs5743557 was associated with reduced TB risk (P=0.006) and the AA/GA genotypes of TLR1 rs5743604 were associated with increased TB risk (P=0.017) when the LTBI group was compared with the TB group. The frequency of TLR1 haplotype rs4833095-rs5743604 CG was significantly higher in the LTBI group than in the TB group (P=0.019877). However, only the relationship between rs5743557 and TB susceptibility remained significant after 1000-fold permutation testing (P=0.023). The meta-analysis suggested that rs5743557_A was associated with decreased TB risk in the Chinese adult population (P<0.001, OR 0.80, 95% CI: 0.72-0.88). No significant gene-gene interactions were found. Conclusions:The results of our study suggest that the tagSNP rs5743557 of TLR1 is associated with the risk of TB.

SUBMITTER: Zhang M

PROVIDER: S-EPMC6409282 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Association of the <i>TLR1</i> variant rs5743557 with susceptibility to tuberculosis.

Zhang Miaomiao M Wang Jing J Wang Yu Y Wu Shouquan S Sandford Andrew J AJ Luo Jun J He Jian-Qing JQ

Journal of thoracic disease 20190201 2

<h4>Background</h4>Toll-like receptor 1 (TLR1) and TLR6 play important roles in the innate immune response against <i>Mycobacterium tuberculosis</i> (M.TB) via interactions with TIR domain-containing adaptor protein (TIRAP) and myeloid differentiation primary response 88 (MYD88). The aim of this study was to investigate the relationship of <i>TLR1, TLR6, MYD88</i> and <i>TIRAP</i> polymorphisms with susceptibility to latent tuberculosis infection (LTBI) and tuberculosis (TB).<h4>Methods</h4>In t ...[more]

PMID: 30963003

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Project description:ImportanceNeuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP.ObjectiveTo identify genetic variants associated with NP susceptibility.Design, setting, and participantsThis genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019.ExposuresIndividuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants.Main outcomes and measuresGWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication.ResultsThis study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated.Conclusions and relevanceTo our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.

Project description:Pulmonary tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease. The risk of developing active TB is in part determined by host genetic factors. Most genetic studies investigating TB susceptibility fail to replicate association signals particularly across diverse populations. South African populations arose because of multi-wave genetic admixture from the indigenous KhoeSan, Bantu-speaking Africans, Europeans, Southeast Asian-and East Asian populations. This has led to complex genetic admixture with heterogenous patterns of linkage disequilibrium and associated traits. As a result, precise estimation of both global and local ancestry is required to prevent both false positive and false-negative associations. Here, 820 individuals from South Africa were genotyped on the SNP-dense Illumina Multi-Ethnic Genotyping Array (∼1.7M SNPs) followed by local and global ancestry inference using RFMix. Local ancestry adjusted allelic association (LAAA) models were utilized owing to the extensive genetic heterogeneity present in this population. Hence, an interaction term, comprising the identification of the minor allele that corresponds to the ancestry present at the specific locus under investigation, was included as a covariate. One SNP (rs28647531) located on chromosome 4q22 was significantly associated with TB susceptibility and displayed a SNP minor allelic effect (G allele, frequency = 0.204) whilst correcting for local ancestry for Bantu-speaking African ancestry (p-value = 5.518 × 10-7; OR = 3.065; SE = 0.224). Although no other variants passed the significant threshold, clear differences were observed between the lead variants identified for each ancestry. Furthermore, the LAAA model robustly captured the source of association signals in multi-way admixed individuals from South Africa and allowed the identification of ancestry-specific disease risk alleles associated with TB susceptibility that have previously been missed.

Dataset Information

Association of the TLR1 variant rs5743557 with susceptibility to tuberculosis.

Publications

Association of the <i>TLR1</i> variant rs5743557 with susceptibility to tuberculosis.

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