Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes

Naomi Takahashi, Mitsuteru Akahoshi, Akira Matsuda, Kouji Ebe, Naoko Inomata, Kazuhiko Obara, Tomomitsu Hirota, Kazuko Nakashima, Makiko Shimizu, Mayumi Tamari, Satoru Doi, Akihiko Miyatake, Tadao Enomoto, Hitoshi Nakashima, Zenro Ikezawa, Taro Shirakawa

研究成果: ジャーナルへの寄稿記事

38 引用 (Scopus)

抄録

Atopic dermatitis (AD) is frequently associated with eosinophilia, highly elevated immunoglobulin E (IgE) levels and increased levels of T-helper 2-type (Th2) cytokines in skin lesions due to infiltrating T cells. Interleukin-12 (IL-12), in combination with interferon-γ (IFN-γ), inhibits IgE synthesis and Th2 cell function. As the IFN-γ-inducing cytokines IL-12 and IL-23 utilize IL-12Rβ1 as part of their receptors, it is possible that polymorphic variants of the IL-12Rβ1 (IL12RB1) gene might determine an individual's susceptibility to AD. Here, we carried out a systemic search for genetic variants of the human IL12RB1 in Japanese subjects and identified 48 genetic variants. In a case-control association study, we found that promoter polymorphisms - 111A/T and - 2C/T were significantly associated with an increased risk of AD under a recessive model. The - 111T-allele frequency in the independent population of child asthmatics was also much higher than that in the control group. In addition, the - 111T/T genotype was progressively more common in AD with high total serum IgE levels in an IgE-level-dependent manner. Deletion analysis of the IL12RB1 promoter suggested that the -265 to -104 region that contained the -111A/T polymorphic site harbored an important regulatory element. Furthermore, we showed that the -111A/T substitution appeared to cause decreased gene transcriptional activity such that cells from -111A/A individuals exhibited higher IL12RB1 mRNA levels than those from -111T allele carriers. Our results suggested that in individuals with the -111T/T genotype, reduced IL-12Rβ1 expression may lead to increased Th2 cytokine production in the skin and contribute to the development of AD and other subsequent allergic diseases.

元の言語英語
ページ(範囲)3149-3159
ページ数11
ジャーナルHuman Molecular Genetics
14
発行部数21
DOI
出版物ステータス出版済み - 11 1 2005

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Atopic Dermatitis
Immunoglobulin E
Phenotype
Interleukin-12
Cytokines
Interferons
Genotype
Interleukin-23
Th2 Cells
Skin
Medical Genetics
Eosinophilia
Gene Frequency
Genes
Case-Control Studies
Alleles
T-Lymphocytes
Control Groups
Messenger RNA
Serum

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

これを引用

Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes. / Takahashi, Naomi; Akahoshi, Mitsuteru; Matsuda, Akira; Ebe, Kouji; Inomata, Naoko; Obara, Kazuhiko; Hirota, Tomomitsu; Nakashima, Kazuko; Shimizu, Makiko; Tamari, Mayumi; Doi, Satoru; Miyatake, Akihiko; Enomoto, Tadao; Nakashima, Hitoshi; Ikezawa, Zenro; Shirakawa, Taro.

:: Human Molecular Genetics, 巻 14, 番号 21, 01.11.2005, p. 3149-3159.

研究成果: ジャーナルへの寄稿記事

Takahashi, N, Akahoshi, M, Matsuda, A, Ebe, K, Inomata, N, Obara, K, Hirota, T, Nakashima, K, Shimizu, M, Tamari, M, Doi, S, Miyatake, A, Enomoto, T, Nakashima, H, Ikezawa, Z & Shirakawa, T 2005, 'Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes', Human Molecular Genetics, 巻. 14, 番号 21, pp. 3149-3159. https://doi.org/10.1093/hmg/ddi347
Takahashi, Naomi ; Akahoshi, Mitsuteru ; Matsuda, Akira ; Ebe, Kouji ; Inomata, Naoko ; Obara, Kazuhiko ; Hirota, Tomomitsu ; Nakashima, Kazuko ; Shimizu, Makiko ; Tamari, Mayumi ; Doi, Satoru ; Miyatake, Akihiko ; Enomoto, Tadao ; Nakashima, Hitoshi ; Ikezawa, Zenro ; Shirakawa, Taro. / Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes. :: Human Molecular Genetics. 2005 ; 巻 14, 番号 21. pp. 3149-3159.
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title = "Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes",
abstract = "Atopic dermatitis (AD) is frequently associated with eosinophilia, highly elevated immunoglobulin E (IgE) levels and increased levels of T-helper 2-type (Th2) cytokines in skin lesions due to infiltrating T cells. Interleukin-12 (IL-12), in combination with interferon-γ (IFN-γ), inhibits IgE synthesis and Th2 cell function. As the IFN-γ-inducing cytokines IL-12 and IL-23 utilize IL-12Rβ1 as part of their receptors, it is possible that polymorphic variants of the IL-12Rβ1 (IL12RB1) gene might determine an individual's susceptibility to AD. Here, we carried out a systemic search for genetic variants of the human IL12RB1 in Japanese subjects and identified 48 genetic variants. In a case-control association study, we found that promoter polymorphisms - 111A/T and - 2C/T were significantly associated with an increased risk of AD under a recessive model. The - 111T-allele frequency in the independent population of child asthmatics was also much higher than that in the control group. In addition, the - 111T/T genotype was progressively more common in AD with high total serum IgE levels in an IgE-level-dependent manner. Deletion analysis of the IL12RB1 promoter suggested that the -265 to -104 region that contained the -111A/T polymorphic site harbored an important regulatory element. Furthermore, we showed that the -111A/T substitution appeared to cause decreased gene transcriptional activity such that cells from -111A/A individuals exhibited higher IL12RB1 mRNA levels than those from -111T allele carriers. Our results suggested that in individuals with the -111T/T genotype, reduced IL-12Rβ1 expression may lead to increased Th2 cytokine production in the skin and contribute to the development of AD and other subsequent allergic diseases.",
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AU - Takahashi, Naomi

AU - Akahoshi, Mitsuteru

AU - Matsuda, Akira

AU - Ebe, Kouji

AU - Inomata, Naoko

AU - Obara, Kazuhiko

AU - Hirota, Tomomitsu

AU - Nakashima, Kazuko

AU - Shimizu, Makiko

AU - Tamari, Mayumi

AU - Doi, Satoru

AU - Miyatake, Akihiko

AU - Enomoto, Tadao

AU - Nakashima, Hitoshi

AU - Ikezawa, Zenro

AU - Shirakawa, Taro

PY - 2005/11/1

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N2 - Atopic dermatitis (AD) is frequently associated with eosinophilia, highly elevated immunoglobulin E (IgE) levels and increased levels of T-helper 2-type (Th2) cytokines in skin lesions due to infiltrating T cells. Interleukin-12 (IL-12), in combination with interferon-γ (IFN-γ), inhibits IgE synthesis and Th2 cell function. As the IFN-γ-inducing cytokines IL-12 and IL-23 utilize IL-12Rβ1 as part of their receptors, it is possible that polymorphic variants of the IL-12Rβ1 (IL12RB1) gene might determine an individual's susceptibility to AD. Here, we carried out a systemic search for genetic variants of the human IL12RB1 in Japanese subjects and identified 48 genetic variants. In a case-control association study, we found that promoter polymorphisms - 111A/T and - 2C/T were significantly associated with an increased risk of AD under a recessive model. The - 111T-allele frequency in the independent population of child asthmatics was also much higher than that in the control group. In addition, the - 111T/T genotype was progressively more common in AD with high total serum IgE levels in an IgE-level-dependent manner. Deletion analysis of the IL12RB1 promoter suggested that the -265 to -104 region that contained the -111A/T polymorphic site harbored an important regulatory element. Furthermore, we showed that the -111A/T substitution appeared to cause decreased gene transcriptional activity such that cells from -111A/A individuals exhibited higher IL12RB1 mRNA levels than those from -111T allele carriers. Our results suggested that in individuals with the -111T/T genotype, reduced IL-12Rβ1 expression may lead to increased Th2 cytokine production in the skin and contribute to the development of AD and other subsequent allergic diseases.

AB - Atopic dermatitis (AD) is frequently associated with eosinophilia, highly elevated immunoglobulin E (IgE) levels and increased levels of T-helper 2-type (Th2) cytokines in skin lesions due to infiltrating T cells. Interleukin-12 (IL-12), in combination with interferon-γ (IFN-γ), inhibits IgE synthesis and Th2 cell function. As the IFN-γ-inducing cytokines IL-12 and IL-23 utilize IL-12Rβ1 as part of their receptors, it is possible that polymorphic variants of the IL-12Rβ1 (IL12RB1) gene might determine an individual's susceptibility to AD. Here, we carried out a systemic search for genetic variants of the human IL12RB1 in Japanese subjects and identified 48 genetic variants. In a case-control association study, we found that promoter polymorphisms - 111A/T and - 2C/T were significantly associated with an increased risk of AD under a recessive model. The - 111T-allele frequency in the independent population of child asthmatics was also much higher than that in the control group. In addition, the - 111T/T genotype was progressively more common in AD with high total serum IgE levels in an IgE-level-dependent manner. Deletion analysis of the IL12RB1 promoter suggested that the -265 to -104 region that contained the -111A/T polymorphic site harbored an important regulatory element. Furthermore, we showed that the -111A/T substitution appeared to cause decreased gene transcriptional activity such that cells from -111A/A individuals exhibited higher IL12RB1 mRNA levels than those from -111T allele carriers. Our results suggested that in individuals with the -111T/T genotype, reduced IL-12Rβ1 expression may lead to increased Th2 cytokine production in the skin and contribute to the development of AD and other subsequent allergic diseases.

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