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

AbhimanyuBose M, Jha P, Indian Genome Variation Consorti - Indian J. Med. Res. (2012)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, India.

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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Linkage disequilibrium (LD) plot and haplotype structure of cytokine gene variants in PTB cases. D’ values are displayed within each diamond, missing values indicate D’ = 100%. Colour scheme gradient indicates r2 values. Length of each block, in kilobases (kb), is shown in brackets.
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Figure 1: Linkage disequilibrium (LD) plot and haplotype structure of cytokine gene variants in PTB cases. D’ values are displayed within each diamond, missing values indicate D’ = 100%. Colour scheme gradient indicates r2 values. Length of each block, in kilobases (kb), is shown in brackets.

Mentions: IFNG polymorphism and PTB susceptibility: After adjusting for multiple testing corrections the IFNG intronic variants at rs1861493 [χ2 =12.089, Pbonferroni = 0.006593, odds ratio (95%CI) =3.8 (1.7 - 8.6)] and rs1861494 (χ2 =10.466, Pbonferroni = 0.01581, odds ratio (95%CI) =3.0 (1.5 - 5.6)] showed a significant risk of developing pulmonary tuberculosis in north Indians with over-representation of the associated A and T alleles among PTB patients, respectively. Investigation of the gene structure and linkage disequilibrium pattern showed haplotypes formed by IFNG variants rs1861493 and rs1861494 which were in high linkage disequilibrium (LD) (Fig.). Three combinations of haplotype were seen namely TC, CC and TA, of which TA haplotype was over-represented in the cases and imposed a two-fold risk of developing pulmonary tuberculosis in north Indians (Table III).


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

AbhimanyuBose M, Jha P, Indian Genome Variation Consorti - Indian J. Med. Res. (2012)

Linkage disequilibrium (LD) plot and haplotype structure of cytokine gene variants in PTB cases. D’ values are displayed within each diamond, missing values indicate D’ = 100%. Colour scheme gradient indicates r2 values. Length of each block, in kilobases (kb), is shown in brackets.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3401711&req=5

Figure 1: Linkage disequilibrium (LD) plot and haplotype structure of cytokine gene variants in PTB cases. D’ values are displayed within each diamond, missing values indicate D’ = 100%. Colour scheme gradient indicates r2 values. Length of each block, in kilobases (kb), is shown in brackets.
Mentions: IFNG polymorphism and PTB susceptibility: After adjusting for multiple testing corrections the IFNG intronic variants at rs1861493 [χ2 =12.089, Pbonferroni = 0.006593, odds ratio (95%CI) =3.8 (1.7 - 8.6)] and rs1861494 (χ2 =10.466, Pbonferroni = 0.01581, odds ratio (95%CI) =3.0 (1.5 - 5.6)] showed a significant risk of developing pulmonary tuberculosis in north Indians with over-representation of the associated A and T alleles among PTB patients, respectively. Investigation of the gene structure and linkage disequilibrium pattern showed haplotypes formed by IFNG variants rs1861493 and rs1861494 which were in high linkage disequilibrium (LD) (Fig.). Three combinations of haplotype were seen namely TC, CC and TA, of which TA haplotype was over-represented in the cases and imposed a two-fold risk of developing pulmonary tuberculosis in north Indians (Table III).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, India.

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.

Show MeSH
Related in: MedlinePlus