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Polymorphisms in the interleukin 18 receptor 1 gene and tuberculosis susceptibility among Chinese.

Zhang J, Zheng L, Zhu D, An H, Yang Y, Liang Y, Zhao W, Ding W, Wu X - PLoS ONE (2014)

Bottom Line: We did not find that any of the 35 tag SNPs individually or as haplotypes was significantly associated with susceptibility to TB, on the basis of multivariable logistic regression analysis with adjustment for age and sex.However, stratification analyses showed that, in those with age 46 years or older, carrying the rs1974675 T allele in the IL18R1 gene had a significantly decreased susceptibility to TB occurrence compared with carrying the C/C genotype (OR = 0.57, P = 5.0×10(-4)).Thus, decreased mRNA levels of IL18R1 due to rs3755276 may partially mediate the increased susceptibility to TB risk.

View Article: PubMed Central - PubMed

Affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.

ABSTRACT
Tuberculosis (TB), an infectious disease caused by infection of Mycobacterium tuberculosis, is a major public health challenge globally. Genetic epidemiological evidence suggests a genetic basis for TB, but the molecular mechanism for a genetic predisposition to TB remains largely unknown. Thirty-five tag single-nucleotide polymorphisms (SNPs) across 11 candidate cytokines and related genes, including IL-12/IFN-γ axis genes (IL12B, IL12RB1, IL18R1, IL27, IFNGR1, IFNGR2 and STAT1), the TNF gene locus (TNF and LTA), IL10, and CCL2, were genotyped using Sequenom's iPLEX assays in 1,032 patients with TB and 1,008 controls of Chinese Han origin. We did not find that any of the 35 tag SNPs individually or as haplotypes was significantly associated with susceptibility to TB, on the basis of multivariable logistic regression analysis with adjustment for age and sex. However, stratification analyses showed that, in those with age 46 years or older, carrying the rs1974675 T allele in the IL18R1 gene had a significantly decreased susceptibility to TB occurrence compared with carrying the C/C genotype (OR = 0.57, P = 5.0×10(-4)). Further analysis indicated that a SNP in absolute linkage disequilibrium with rs1974675, rs3755276, is located within a CpG dinucleotide and showed hypomethylation in controls than in patients (19.6% vs. 31.4%; P = 1.0×10(-4)) and genotype-specific DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels. In addition, DNA methylation levels were significantly inversely correlated with mRNA levels. Thus, decreased mRNA levels of IL18R1 due to rs3755276 may partially mediate the increased susceptibility to TB risk.

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Related in: MedlinePlus

SNPs in the IL18R1 gene, DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels.(A) The upper panel indicates the tag SNPs across the IL18R1 gene and the linkage disequilibrium (LD) structure in the Chinese case-control population. Pairwise LD (measured by r2) between SNPs is indicated by the color of individual squares in the triangular graphic, the squares with the deepest color have r2 = 1. The lower panel indicates the five CpG sites at the IL18R1 promoter (−814, −662, −660, −592, and −516 bp), where a SNP in absolute LD with rs1974675 (r2 = 1 in CHB), rs3755276, is located within the second CpG site (−662 bp). Position +1 is determined by the start codon. (B) Correlation between methylation status at two CpG sites next to each other (−662 and −660 bp) and genotypes at rs3755276 in 18 patients with TB and 18 controls. DNA methylation was analysed using the EpiTYPER platform (Sequenom) which recognizes the two CpG sites (−662 and −660 bp) as one methylation signal. (C) Correlation between methylation status of the CpG site at −662 bp and genotypes at rs3755276 in additional 30 healthy controls. DNA methylation was analysed at a single nucleotide level by quantitative pyrosequencing in a Biotage PSQ 96MA system. (D) Correlation between IL18R1 mRNA levels and genotypes at rs3755276 in the 30 healthy controls. (E) Correlation between IL18R1 mRNA levels and DNA methylation at −662 bp (rs3755276) in the 30 healthy controls. A Pearson's test was used, and the correlation coefficient (ρ) and the two-tailed significance are shown. Outliers are marked with a circle on the boxplot. Error bars indicate means ±SD.
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pone-0110734-g001: SNPs in the IL18R1 gene, DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels.(A) The upper panel indicates the tag SNPs across the IL18R1 gene and the linkage disequilibrium (LD) structure in the Chinese case-control population. Pairwise LD (measured by r2) between SNPs is indicated by the color of individual squares in the triangular graphic, the squares with the deepest color have r2 = 1. The lower panel indicates the five CpG sites at the IL18R1 promoter (−814, −662, −660, −592, and −516 bp), where a SNP in absolute LD with rs1974675 (r2 = 1 in CHB), rs3755276, is located within the second CpG site (−662 bp). Position +1 is determined by the start codon. (B) Correlation between methylation status at two CpG sites next to each other (−662 and −660 bp) and genotypes at rs3755276 in 18 patients with TB and 18 controls. DNA methylation was analysed using the EpiTYPER platform (Sequenom) which recognizes the two CpG sites (−662 and −660 bp) as one methylation signal. (C) Correlation between methylation status of the CpG site at −662 bp and genotypes at rs3755276 in additional 30 healthy controls. DNA methylation was analysed at a single nucleotide level by quantitative pyrosequencing in a Biotage PSQ 96MA system. (D) Correlation between IL18R1 mRNA levels and genotypes at rs3755276 in the 30 healthy controls. (E) Correlation between IL18R1 mRNA levels and DNA methylation at −662 bp (rs3755276) in the 30 healthy controls. A Pearson's test was used, and the correlation coefficient (ρ) and the two-tailed significance are shown. Outliers are marked with a circle on the boxplot. Error bars indicate means ±SD.

Mentions: The stratification had no significant effects on the results obtained in analyses stratified for sex (P values for heterogeneity >0.01; data not shown). However, when conducting age-stratified analyses on the basis of mean age in controls (<46 or ≥46 years), we found evidence of heterogeneity for two SNPs in the IL18R1 gene locus (rs1974675 and rs6758936, Table 1, Fig. 1A and Table S3). In the older group, the individuals carrying the rs1974675 T allele had a significantly decreased susceptibility to TB compared with those carrying the C/C genotype (OR = 0.57; 95% CI = 0.41–0.79, P = 0.00050); for rs6758936, the individuals carrying the A allele had a significantly decreased susceptibility to TB compared with those carrying the G/G genotype (OR = 0.66; 95% CI = 0.47–0.88, P = 0.0053). The association of rs1974675 remained significant even after Bonferroni correction for multiple testing. By contrast, the associations were not significant in younger groups. Case-only analysis in the older patients with TB showed no significant difference on age at TB diagnosis for the protective allele carriers and the at-risk homozygotes (P = 0.46 and P = 0.73 for rs1974675 and rs6758936, respectively; Table S4).


Polymorphisms in the interleukin 18 receptor 1 gene and tuberculosis susceptibility among Chinese.

Zhang J, Zheng L, Zhu D, An H, Yang Y, Liang Y, Zhao W, Ding W, Wu X - PLoS ONE (2014)

SNPs in the IL18R1 gene, DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels.(A) The upper panel indicates the tag SNPs across the IL18R1 gene and the linkage disequilibrium (LD) structure in the Chinese case-control population. Pairwise LD (measured by r2) between SNPs is indicated by the color of individual squares in the triangular graphic, the squares with the deepest color have r2 = 1. The lower panel indicates the five CpG sites at the IL18R1 promoter (−814, −662, −660, −592, and −516 bp), where a SNP in absolute LD with rs1974675 (r2 = 1 in CHB), rs3755276, is located within the second CpG site (−662 bp). Position +1 is determined by the start codon. (B) Correlation between methylation status at two CpG sites next to each other (−662 and −660 bp) and genotypes at rs3755276 in 18 patients with TB and 18 controls. DNA methylation was analysed using the EpiTYPER platform (Sequenom) which recognizes the two CpG sites (−662 and −660 bp) as one methylation signal. (C) Correlation between methylation status of the CpG site at −662 bp and genotypes at rs3755276 in additional 30 healthy controls. DNA methylation was analysed at a single nucleotide level by quantitative pyrosequencing in a Biotage PSQ 96MA system. (D) Correlation between IL18R1 mRNA levels and genotypes at rs3755276 in the 30 healthy controls. (E) Correlation between IL18R1 mRNA levels and DNA methylation at −662 bp (rs3755276) in the 30 healthy controls. A Pearson's test was used, and the correlation coefficient (ρ) and the two-tailed significance are shown. Outliers are marked with a circle on the boxplot. Error bars indicate means ±SD.
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Show All Figures
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pone-0110734-g001: SNPs in the IL18R1 gene, DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels.(A) The upper panel indicates the tag SNPs across the IL18R1 gene and the linkage disequilibrium (LD) structure in the Chinese case-control population. Pairwise LD (measured by r2) between SNPs is indicated by the color of individual squares in the triangular graphic, the squares with the deepest color have r2 = 1. The lower panel indicates the five CpG sites at the IL18R1 promoter (−814, −662, −660, −592, and −516 bp), where a SNP in absolute LD with rs1974675 (r2 = 1 in CHB), rs3755276, is located within the second CpG site (−662 bp). Position +1 is determined by the start codon. (B) Correlation between methylation status at two CpG sites next to each other (−662 and −660 bp) and genotypes at rs3755276 in 18 patients with TB and 18 controls. DNA methylation was analysed using the EpiTYPER platform (Sequenom) which recognizes the two CpG sites (−662 and −660 bp) as one methylation signal. (C) Correlation between methylation status of the CpG site at −662 bp and genotypes at rs3755276 in additional 30 healthy controls. DNA methylation was analysed at a single nucleotide level by quantitative pyrosequencing in a Biotage PSQ 96MA system. (D) Correlation between IL18R1 mRNA levels and genotypes at rs3755276 in the 30 healthy controls. (E) Correlation between IL18R1 mRNA levels and DNA methylation at −662 bp (rs3755276) in the 30 healthy controls. A Pearson's test was used, and the correlation coefficient (ρ) and the two-tailed significance are shown. Outliers are marked with a circle on the boxplot. Error bars indicate means ±SD.
Mentions: The stratification had no significant effects on the results obtained in analyses stratified for sex (P values for heterogeneity >0.01; data not shown). However, when conducting age-stratified analyses on the basis of mean age in controls (<46 or ≥46 years), we found evidence of heterogeneity for two SNPs in the IL18R1 gene locus (rs1974675 and rs6758936, Table 1, Fig. 1A and Table S3). In the older group, the individuals carrying the rs1974675 T allele had a significantly decreased susceptibility to TB compared with those carrying the C/C genotype (OR = 0.57; 95% CI = 0.41–0.79, P = 0.00050); for rs6758936, the individuals carrying the A allele had a significantly decreased susceptibility to TB compared with those carrying the G/G genotype (OR = 0.66; 95% CI = 0.47–0.88, P = 0.0053). The association of rs1974675 remained significant even after Bonferroni correction for multiple testing. By contrast, the associations were not significant in younger groups. Case-only analysis in the older patients with TB showed no significant difference on age at TB diagnosis for the protective allele carriers and the at-risk homozygotes (P = 0.46 and P = 0.73 for rs1974675 and rs6758936, respectively; Table S4).

Bottom Line: We did not find that any of the 35 tag SNPs individually or as haplotypes was significantly associated with susceptibility to TB, on the basis of multivariable logistic regression analysis with adjustment for age and sex.However, stratification analyses showed that, in those with age 46 years or older, carrying the rs1974675 T allele in the IL18R1 gene had a significantly decreased susceptibility to TB occurrence compared with carrying the C/C genotype (OR = 0.57, P = 5.0×10(-4)).Thus, decreased mRNA levels of IL18R1 due to rs3755276 may partially mediate the increased susceptibility to TB risk.

View Article: PubMed Central - PubMed

Affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.

ABSTRACT
Tuberculosis (TB), an infectious disease caused by infection of Mycobacterium tuberculosis, is a major public health challenge globally. Genetic epidemiological evidence suggests a genetic basis for TB, but the molecular mechanism for a genetic predisposition to TB remains largely unknown. Thirty-five tag single-nucleotide polymorphisms (SNPs) across 11 candidate cytokines and related genes, including IL-12/IFN-γ axis genes (IL12B, IL12RB1, IL18R1, IL27, IFNGR1, IFNGR2 and STAT1), the TNF gene locus (TNF and LTA), IL10, and CCL2, were genotyped using Sequenom's iPLEX assays in 1,032 patients with TB and 1,008 controls of Chinese Han origin. We did not find that any of the 35 tag SNPs individually or as haplotypes was significantly associated with susceptibility to TB, on the basis of multivariable logistic regression analysis with adjustment for age and sex. However, stratification analyses showed that, in those with age 46 years or older, carrying the rs1974675 T allele in the IL18R1 gene had a significantly decreased susceptibility to TB occurrence compared with carrying the C/C genotype (OR = 0.57, P = 5.0×10(-4)). Further analysis indicated that a SNP in absolute linkage disequilibrium with rs1974675, rs3755276, is located within a CpG dinucleotide and showed hypomethylation in controls than in patients (19.6% vs. 31.4%; P = 1.0×10(-4)) and genotype-specific DNA methylation at the IL18R1 promoter and IL18R1 mRNA levels. In addition, DNA methylation levels were significantly inversely correlated with mRNA levels. Thus, decreased mRNA levels of IL18R1 due to rs3755276 may partially mediate the increased susceptibility to TB risk.

Show MeSH
Related in: MedlinePlus