title: Polymorphisms in the interleukin 18 receptor 1 gene and tuberculosis susceptibility among Chinese.
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.
authors.affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.
authors.forename: Junxian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.
authors.forename: Donglin
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.
authors.forename: Huiru
authors.initials: H
authors.lastname: An
authors.affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.
authors.forename: Yourong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, P. R. China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ding
authors.affiliation: Army Tuberculosis Prevention and Control Key Laboratory, Institute for Tuberculosis Research, the 309th Hospital of Chinese PLA, Beijing, P. R. China.
authors.forename: Xueqiong
authors.initials: X
authors.lastname: Wu
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics* / Q000378:metabolism
chemical_list: D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma