Toll-Like Receptor-1 Single-Nucleotide Polymorphism 1805T/G Is Associated With Predisposition to Multibacillary Tuberculosis.

Raphaela Honorato Barletta-Naveca,Vanessa Alves De Almeida,George Allan Villarouco Da Silva,Rajendranath Ramasawmy,Mauricio Morishi Ogusku,Aya Sadahiro,Felipe Gomes Naveca,Antonio Luiz Boechat,Jorge Ivan Rebelo Porto

doi:10.3389/fimmu.2018.01455

Raphaela Honorato Barletta-Naveca, Vanessa Alves De Almeida + Show 7 more

Open Access

https://doi.org/10.3389/fimmu.2018.01455

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Abstract

Tuberculosis (TB), caused by mycobacterial species of the Mycobacterium tuberculosis complex, is a serious global health issue. Brazil is among the 22 countries with the highest number of TB cases, and the state of Amazonas has the highest incidence of TB cases in the country. Toll-like receptors (TLRs) are important pattern recognition receptors of the innate immunity and play a key role in orchestrating an effective immune response. We investigated whether the single-nucleotide polymorphisms (SNPs) 1805T/G TLR1, 2258G/A TLR2, 896A/G and 1196C/T of TLR4, 745T/C TLR6, and −1237A/G and −1486A/G of TLR9 are associated with the predisposition to TB and/or bacillary load. The SNPs genotyping was performed by nucleotide sequencing in 263 TB patients and 232 healthy controls residing in the state of Amazonas. Alleles and genotypes frequencies were similar between patients and healthy individuals for most of the investigated SNPs. Stratification of the TB patients according to their bacillary load showed that the genotype 1805TT TLR1 (rs5743618) was prevalent among paucibacillary patients [odds ratio (OR) = 0.38; 95% confidence interval (CI) = 0.19–0.76; p = 0.009] while the genotype 1805TG was common among multibacillary patients (OR = 3.72; CI = 1.65–8.4; p = 0.004). Comparison of demographic characteristics of patients to controls showed that TB is strongly associated with smoking (OR = 6.55; 95% CI = 3.2–13.6; p < 0.0001); alcohol use disorder (OR = 7.14; 95% CI = 3.7–13.9; p < 0.0001); and male gender (OR = 3.66; 95% CI = 2.52–5.3; p < 0.0001). Multivariate logistic regression demonstrated that alcoholism (OR = 2.93; 95% CI = 1.05–8.16; p = 0.03) and the 1805G allele (OR = 2.75; 95% CI = 1.33–5.7; p = 0.006) are predictive variables for multibacillary TB. Altogether, we suggest that the TLR1 1805G allele may be a relevant immunogenetic factor for the epidemiology of TB together with environmental, sociodemographic, and behavioral factors.

Highlights

Tuberculosis (TB) is a contagious disease caused by mycobacteria of the Mycobacterium tuberculosis complex
We investigated whether the single-nucleotide polymorphisms (SNPs) rs5743618 (1805T/G) of TLR1, rs5743708 (2258G/A) of TLR2, rs4986790 (896A/G) and rs4986791 (1196C/T) of TLR4, rs5743810 (745C/T) of TLR6, and the rs5743836 (−1237A/G) and rs187084 (−1486A/G) of TLR9 are associated with TB and with the bacterial load
Comparison of genotypes and allele frequencies of all the SNPs between multibacillary and paucibacillary TB revealed that the genotype 1805TT TLR1 was prevalent among paucibacillary patients (OR = 0.38; 95% confidence interval (CI) = 0.19–0.76; p = 0.009) while the genotype 1805TG was common among multibacillary patients (OR = 3.72; CI = 1.65–8.4; p = 0.004)

Summary

Introduction

Tuberculosis (TB) is a contagious disease caused by mycobacteria of the Mycobacterium tuberculosis complex. The most common clinical form is pulmonary TB. TB causes a serious public health burden worldwide and its control remains a major challenge for the scientific community and TB control programs globally. 10 million people worldwide suffered from TB each year [1]. Brazil is one of the 30 countries considered a priority for TB control as more than 69 thousand new cases occur annually. The state of Amazonas has the highest incidence of TB in the country with 67.2/100 thousand inhabitants [1, 2]

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