Influence of interleukin-12 receptor β1 polymorphisms on tuberculosis

Mitsuteru Akahoshi, Hitoshi Nakashima, Katsuhisa Miyake, Yasushi Inoue, Sakiko Shimizu, Yosuke Tanaka, Kaoru Okada, Takeshi Otsuka, Mine Harada

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42 Citations (Scopus)


Host genetic factors may be important determinants of susceptibility to tuberculosis, and several candidate gene polymorphisms have been shown to date. A series of recent reports concerning rare human deficiencies in the type-1 cytokine pathway suggest that more subtle variants of relevant genes may also contribute to susceptibility to tuberculosis at the general population level. To investigate whether polymorphisms in the interleukin-12 receptor (IL-12R) gene predispose individuals to tuberculosis, we studied these genes by single-strand conformational polymorphism analysis and direct sequencing. Although no common polymorphisms could be identified in the IL-12Rβ2 gene (IL-12RB2), we confirmed four single nucleotide polymorphisms (SNPs; 641A→G, 684C→T, 1094T→C, and 1132G→C) causing three missense variants (Q214R, M365T, G378R) and one synonymous substitution in the extracellular domain of the IL-12Rβ1 gene (IL12RB1). All SNPs were in almost perfect linkage disequilibrium (D′=0.98), and two common haplotypes of IL12RB1 (allele 1: Q214-M365-G378; allele 2: R214-T365-R378) were revealed. Polymerase chain reaction/restriction fragment length polymorphism and sequence analyses were used to type IL12RB1 polymorphisms in 98 patients with tuberculosis and 197 healthy controls in Japanese populations. In our case-control association study of tuberculosis, the R214-T365-R378 allele (allele 2) was over-represented in patients with tuberculosis, and homozygosity for R214-T365-R378 (the 2/2 genotype) was significantly associated with tuberculosis (odds ratio: 2.45; 95% CI: 1.20-4.99; P =0.013). In healthy subjects, homozygotes for R214-T365-R378 had lower levels of IL-12-induced signaling, according to differences in cellular responses to IL-12 between two haplotypes. These data suggest that the R214-T365-R378 allele, i.e., variation in IL12RB1, contribute to tuberculosis susceptibility in the Japanese population. This genetic variation may predispose individuals to tuberculosis infection by diminishing receptor responsiveness to IL-12 and to IL-23, leading to partial dysfunction of interferon-γ-mediated immunity.

Original languageEnglish
Pages (from-to)237-243
Number of pages7
JournalHuman Genetics
Issue number3
Publication statusPublished - Mar 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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