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Footprints of genetic susceptibility to pulmonary tuberculosis: cytokine gene variants in north Indians.

ABSTRACT: BACKGROUND & OBJECTIVES: Tuberculosis is (TB) responsible for high morbidity and mortality worldwide. Cytokines play a major role in defense against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding the various pro- and anti-inflammatory cytokines have been associated with tuberculosis susceptibility. In this study we examined association of 25 sequence polymorphisms in six candidate cytokine genes namely IFNG, TNFB, IL4, IL1RA, IL1B and IL12 and their related haplotypes with risk of developing pulmonary tuberculosis (PTB) among north Indians. METHODS: Pulmonary TB (n=110) patients and 215 healthy controls (HC) from north India were genotyped. Purified multiplex PCR products were subjected to mass spectrometry using Sequenom MassARRAY platform to generate the genotypes in a population-based case-control study. RESULTS: Using multiple corrections, significant overall risk against PTB was observed at seven loci which included variants in IFNG at rs1861493 and rs1861494; IL1RA at rs4252019, IL4 variant rs2070874, IL12 variants rs3212220, rs2853694 and TNFB variant rs1041981. Analysis of gene structure revealed two haplotype blocks formed by IFNG variants rs1861493 and rs1861494. The TA haplotype was significantly over-represented (P=0.011) in the cases showing a two-fold risk in the current population (Odds ratio=1.59 CI=1.101 to 2.297) and TNFB variants at rs2229094 and rs1041981 contributed to two haplotypes which were in strong linkage disequilibrium (LD) with AT haplotype showing a three-fold risk (P=0.0011, Odds ratio=3, CI=0.1939 to 0.7445) of developing PTB in north Indians. INTERPRETATION & CONCLUSIONS: Our study showed six novel associations of cytokine gene variants with susceptibility to PTB in north Indians. Variants of IFNG and TNFB emerged as factors imposing a significant risk of developing PTB in north Indians apart from risk indicated by IL1RA, IL4 and IL12.

SUBMITTER: Abhimanyu

PROVIDER: S-EPMC3401711 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Footprints of genetic susceptibility to pulmonary tuberculosis: cytokine gene variants in north Indians.

Bose Mridula M Jha Pankaj P

The Indian journal of medical research 20120501 5

<h4>Background & objectives</h4>Tuberculosis is (TB) responsible for high morbidity and mortality worldwide. Cytokines play a major role in defense against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding the various pro- and anti-inflammatory cytokines have been associated with tuberculosis susceptibility. In this study we examined association of 25 sequence polymorphisms in six candidate cytokine genes namely IFNG, TNFB, IL4, IL1RA, IL1B and IL12 and their related hapl ...[more]

PMID: 22771610

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Project description:BACKGROUND:The two major class A scavenger receptors are scavenger receptor A (SRA), which is constitutively expressed on most macrophage populations, and macrophage receptor with collagenous structure (MARCO), which is constitutively expressed on a more restricted subset of macrophages, (e.g. alveolar macrophages) but whose expression increases on most macrophages during the course of infection. Although the primary role of SRA appears to be clearance of modified host proteins and lipids, mice defective in expression of either MARCO or SRA are immunocompromised in multiple models of infection and in vitro assays, the scavenger receptors have been demonstrated to bind bacteria and to enhance pro-inflammatory signalling to many bacterial lung pathogens; however their importance in Mycobacterium tuberculosis infection, is less clear. METHODS:To determine whether polymorphisms in either SRA or MARCO were associated with tuberculosis, a case-control study of was performed. DNA samples from newly-detected, smear-positive, pulmonary tuberculosis cases were collected from The Gambia. Controls for this study consisted of DNA from cord bloods obtained from routine births at local Gambian health clinics. Informed written consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint The Gambian Government/MRC Joint Ethics Committee. RESULTS:We studied the frequencies of 25 polymorphisms of MSR1 (SRA) and 22 in MARCO in individuals with tuberculosis (n=1284) and matched controls (n=1349). No SNPs within the gene encoding or within 1 kb of the promoter sequence of MSR1 were associated with either susceptibility or resistance to tuberculosis. Three SNPs in MARCO (rs4491733, Mantel-Haenszel 2x2 ?2 = 6.5, p = 0.001, rs12998782, Mantel-Haenszel 2x2 ?2 = 6.59, p = 0.001, rs13389814 Mantel-Haenszel 2x2 ?2 = 6.9, p = 0.0009) were associated with susceptibility to tuberculosis and one (rs7559955, Mantel-Haenszel 2x2 ?2 = 6.9, p = 0.0009) was associated with resistance to tuberculosis. CONCLUSIONS:These findings identify MARCO as a potentially important receptor in the host response to tuberculosis.

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Footprints of genetic susceptibility to pulmonary tuberculosis: cytokine gene variants in north Indians.

Publications

Footprints of genetic susceptibility to pulmonary tuberculosis: cytokine gene variants in north Indians.

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