TY - JOUR
T1 - Influence of interleukin-12 receptor β1 polymorphisms on tuberculosis
AU - Akahoshi, Mitsuteru
AU - Nakashima, Hitoshi
AU - Miyake, Katsuhisa
AU - Inoue, Yasushi
AU - Shimizu, Sakiko
AU - Tanaka, Yosuke
AU - Okada, Kaoru
AU - Otsuka, Takeshi
AU - Harada, Mine
N1 - Funding Information:
Acknowledgements We thank Ms. Yuko Furukawa for her skillful technical assistance, and Drs. Tomoaki Iwanaga and Kiyoshi Ninomiya for their assistance in this study. We are especially grateful to Dr. Motosuke Hanada for his encouragement and helpful advice. This research was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT).
PY - 2003/3
Y1 - 2003/3
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-002-0873-5
DO - 10.1007/s00439-002-0873-5
M3 - Article
C2 - 12596048
AN - SCOPUS:0037361308
SN - 0340-6717
VL - 112
SP - 237
EP - 243
JO - Human Genetics
JF - Human Genetics
IS - 3
ER -
