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

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      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.

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      Most cited references 30

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      Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.
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        Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.
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          Functional diversity of helper T lymphocytes.

          The existence of subsets of CD4+ helper T lymphocytes that differ in their cytokine secretion patterns and effector functions provides a framework for understanding the heterogeneity of normal and pathological immune responses. Defining the cellular and molecular mechanisms of helper-T-cell differentiation should lead to rational strategies for manipulating immune responses for prophylaxis and therapy.
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            Author and article information

            Affiliations
            Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, India
            [* ] Department of Genomics & Molecular Medicine, CSIR-Institute of Genomics & Integrative Biology, Delhi, India
            Author notes
            Reprint requests: Prof. Mridula Bose, Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110 007, India e-mail: mridulabose@ 123456hotmail.com
            Journal
            Indian J Med Res
            Indian J. Med. Res
            IJMR
            The Indian Journal of Medical Research
            Medknow Publications & Media Pvt Ltd (India )
            0971-5916
            May 2012
            : 135
            : 5
            : 763-770
            3401711
            22771610
            IJMR-135-763
            Copyright: © The Indian Journal of Medical Research

            This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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