Functional haplotypes of IL-12B are associated with childhood atopic asthma

Tomomitsu Hirota, Yoichi Suzuki, Koichi Hasegawa, Kazuhiko Obara, Akira Matsuda, Mitsuteru Akahoshi, Kazuko Nakashima, Lei Cheng, Naomi Takahashi, Makiko Shimizu, Satoru Doi, Kimie Fujita, Tadao Enomoto, Motohiro Ebisawa, Shigemi Yoshihara, Yusuke Nakamura, Fumio Kishi, Taro Shirakawa, Mayumi Tamari

Research output: Contribution to journalArticle

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Abstract

Background: IL-12 is a heterodimeric proinflammatory cytokine that forms a link between innate and adaptive immunity. Although associations between polymorphisms of IL-12B on chromosome 5q31-33 and asthma have been reported, the genetic influences of the polymorphisms and haplotype of IL-12B are unclear. Objective: To examine whether polymorphisms in IL-12B are associated with childhood atopic asthma in a Japanese population. Methods: We identified a total of 13 polymorphisms and characterized the linkage disequilibrium mapping of the gene. Three variants in the promoter and 3′ untranslated region were genotyped, and we conducted case-control and case-only association studies between those variants and asthma-related phenotypes (childhood atopic asthma, n = 297; normal controls, n = 555). Haplotype association analysis and functional analysis of these variants were also performed. Results: 3′ Untranslated region 10841C>A was significantly associated with the risk of childhood atopic asthma (P = .00062). The -6415 promoter variant, in linkage disequilibrium with the 10841C>A (D′ = 0.78 and r2 = 0.61), was also marginally associated with childhood atopic asthma (P = .051). We analyzed the 2-locus haplotype by using these 2 polymorphisms and found a positive association with haplotype CTCTAA-C (-6415 CTCTAA and 10841C; P = .00078). Furthermore, 10841C>A affects the stability of transcripts, and promoter variant -6415GC enhances the transcriptional level of IL-12B. Conclusion: Our results imply that functional haplotype CTCTAA-C, which affects the instability of transcripts and the lower transcriptional level of IL-12B, has a protective effect in childhood atopic asthma. On the basis of these findings, the IL-12B gene might be involved in the development of atopic asthma through functional genetic polymorphisms.

Original languageEnglish
Pages (from-to)789-795
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume116
Issue number4
DOIs
Publication statusPublished - Oct 1 2005
Externally publishedYes

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Haplotypes
Asthma
Linkage Disequilibrium
3' Untranslated Regions
Chromosome Mapping
Adaptive Immunity
Genetic Polymorphisms
Interleukin-12
Innate Immunity
Genes
Chromosomes
Cytokines
Phenotype
Population

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Functional haplotypes of IL-12B are associated with childhood atopic asthma. / Hirota, Tomomitsu; Suzuki, Yoichi; Hasegawa, Koichi; Obara, Kazuhiko; Matsuda, Akira; Akahoshi, Mitsuteru; Nakashima, Kazuko; Cheng, Lei; Takahashi, Naomi; Shimizu, Makiko; Doi, Satoru; Fujita, Kimie; Enomoto, Tadao; Ebisawa, Motohiro; Yoshihara, Shigemi; Nakamura, Yusuke; Kishi, Fumio; Shirakawa, Taro; Tamari, Mayumi.

In: Journal of Allergy and Clinical Immunology, Vol. 116, No. 4, 01.10.2005, p. 789-795.

Research output: Contribution to journalArticle

Hirota, T, Suzuki, Y, Hasegawa, K, Obara, K, Matsuda, A, Akahoshi, M, Nakashima, K, Cheng, L, Takahashi, N, Shimizu, M, Doi, S, Fujita, K, Enomoto, T, Ebisawa, M, Yoshihara, S, Nakamura, Y, Kishi, F, Shirakawa, T & Tamari, M 2005, 'Functional haplotypes of IL-12B are associated with childhood atopic asthma', Journal of Allergy and Clinical Immunology, vol. 116, no. 4, pp. 789-795. https://doi.org/10.1016/j.jaci.2005.06.010
Hirota, Tomomitsu ; Suzuki, Yoichi ; Hasegawa, Koichi ; Obara, Kazuhiko ; Matsuda, Akira ; Akahoshi, Mitsuteru ; Nakashima, Kazuko ; Cheng, Lei ; Takahashi, Naomi ; Shimizu, Makiko ; Doi, Satoru ; Fujita, Kimie ; Enomoto, Tadao ; Ebisawa, Motohiro ; Yoshihara, Shigemi ; Nakamura, Yusuke ; Kishi, Fumio ; Shirakawa, Taro ; Tamari, Mayumi. / Functional haplotypes of IL-12B are associated with childhood atopic asthma. In: Journal of Allergy and Clinical Immunology. 2005 ; Vol. 116, No. 4. pp. 789-795.
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abstract = "Background: IL-12 is a heterodimeric proinflammatory cytokine that forms a link between innate and adaptive immunity. Although associations between polymorphisms of IL-12B on chromosome 5q31-33 and asthma have been reported, the genetic influences of the polymorphisms and haplotype of IL-12B are unclear. Objective: To examine whether polymorphisms in IL-12B are associated with childhood atopic asthma in a Japanese population. Methods: We identified a total of 13 polymorphisms and characterized the linkage disequilibrium mapping of the gene. Three variants in the promoter and 3′ untranslated region were genotyped, and we conducted case-control and case-only association studies between those variants and asthma-related phenotypes (childhood atopic asthma, n = 297; normal controls, n = 555). Haplotype association analysis and functional analysis of these variants were also performed. Results: 3′ Untranslated region 10841C>A was significantly associated with the risk of childhood atopic asthma (P = .00062). The -6415 promoter variant, in linkage disequilibrium with the 10841C>A (D′ = 0.78 and r2 = 0.61), was also marginally associated with childhood atopic asthma (P = .051). We analyzed the 2-locus haplotype by using these 2 polymorphisms and found a positive association with haplotype CTCTAA-C (-6415 CTCTAA and 10841C; P = .00078). Furthermore, 10841C>A affects the stability of transcripts, and promoter variant -6415GC enhances the transcriptional level of IL-12B. Conclusion: Our results imply that functional haplotype CTCTAA-C, which affects the instability of transcripts and the lower transcriptional level of IL-12B, has a protective effect in childhood atopic asthma. On the basis of these findings, the IL-12B gene might be involved in the development of atopic asthma through functional genetic polymorphisms.",
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T1 - Functional haplotypes of IL-12B are associated with childhood atopic asthma

AU - Hirota, Tomomitsu

AU - Suzuki, Yoichi

AU - Hasegawa, Koichi

AU - Obara, Kazuhiko

AU - Matsuda, Akira

AU - Akahoshi, Mitsuteru

AU - Nakashima, Kazuko

AU - Cheng, Lei

AU - Takahashi, Naomi

AU - Shimizu, Makiko

AU - Doi, Satoru

AU - Fujita, Kimie

AU - Enomoto, Tadao

AU - Ebisawa, Motohiro

AU - Yoshihara, Shigemi

AU - Nakamura, Yusuke

AU - Kishi, Fumio

AU - Shirakawa, Taro

AU - Tamari, Mayumi

PY - 2005/10/1

Y1 - 2005/10/1

N2 - Background: IL-12 is a heterodimeric proinflammatory cytokine that forms a link between innate and adaptive immunity. Although associations between polymorphisms of IL-12B on chromosome 5q31-33 and asthma have been reported, the genetic influences of the polymorphisms and haplotype of IL-12B are unclear. Objective: To examine whether polymorphisms in IL-12B are associated with childhood atopic asthma in a Japanese population. Methods: We identified a total of 13 polymorphisms and characterized the linkage disequilibrium mapping of the gene. Three variants in the promoter and 3′ untranslated region were genotyped, and we conducted case-control and case-only association studies between those variants and asthma-related phenotypes (childhood atopic asthma, n = 297; normal controls, n = 555). Haplotype association analysis and functional analysis of these variants were also performed. Results: 3′ Untranslated region 10841C>A was significantly associated with the risk of childhood atopic asthma (P = .00062). The -6415 promoter variant, in linkage disequilibrium with the 10841C>A (D′ = 0.78 and r2 = 0.61), was also marginally associated with childhood atopic asthma (P = .051). We analyzed the 2-locus haplotype by using these 2 polymorphisms and found a positive association with haplotype CTCTAA-C (-6415 CTCTAA and 10841C; P = .00078). Furthermore, 10841C>A affects the stability of transcripts, and promoter variant -6415GC enhances the transcriptional level of IL-12B. Conclusion: Our results imply that functional haplotype CTCTAA-C, which affects the instability of transcripts and the lower transcriptional level of IL-12B, has a protective effect in childhood atopic asthma. On the basis of these findings, the IL-12B gene might be involved in the development of atopic asthma through functional genetic polymorphisms.

AB - Background: IL-12 is a heterodimeric proinflammatory cytokine that forms a link between innate and adaptive immunity. Although associations between polymorphisms of IL-12B on chromosome 5q31-33 and asthma have been reported, the genetic influences of the polymorphisms and haplotype of IL-12B are unclear. Objective: To examine whether polymorphisms in IL-12B are associated with childhood atopic asthma in a Japanese population. Methods: We identified a total of 13 polymorphisms and characterized the linkage disequilibrium mapping of the gene. Three variants in the promoter and 3′ untranslated region were genotyped, and we conducted case-control and case-only association studies between those variants and asthma-related phenotypes (childhood atopic asthma, n = 297; normal controls, n = 555). Haplotype association analysis and functional analysis of these variants were also performed. Results: 3′ Untranslated region 10841C>A was significantly associated with the risk of childhood atopic asthma (P = .00062). The -6415 promoter variant, in linkage disequilibrium with the 10841C>A (D′ = 0.78 and r2 = 0.61), was also marginally associated with childhood atopic asthma (P = .051). We analyzed the 2-locus haplotype by using these 2 polymorphisms and found a positive association with haplotype CTCTAA-C (-6415 CTCTAA and 10841C; P = .00078). Furthermore, 10841C>A affects the stability of transcripts, and promoter variant -6415GC enhances the transcriptional level of IL-12B. Conclusion: Our results imply that functional haplotype CTCTAA-C, which affects the instability of transcripts and the lower transcriptional level of IL-12B, has a protective effect in childhood atopic asthma. On the basis of these findings, the IL-12B gene might be involved in the development of atopic asthma through functional genetic polymorphisms.

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