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Human Molecular Genetics Advance Access originally published online on September 13, 2005
Human Molecular Genetics 2005 14(21):3149-3159; doi:10.1093/hmg/ddi347
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© The Author 2005. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

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

Naomi Takahashi1,2, Mitsuteru Akahoshi1,3,*, Akira Matsuda1, Kouji Ebe4, Naoko Inomata5, Kazuhiko Obara1,6, Tomomitsu Hirota1, Kazuko Nakashima1,7, Makiko Shimizu1, Mayumi Tamari1, Satoru Doi8, Akihiko Miyatake9, Tadao Enomoto10, Hitoshi Nakashima3, Zenro Ikezawa5 and Taro Shirakawa1,7

1Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN, Kanagawa 230-0045, Japan, 2Department of Dermatology, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan, 3Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 4Takao Hospital, Kyoto, Japan, 5Department of Dermatology, Yokohama City University School of Medicine, Kanagawa, Japan, 6Hitachi Chemical Co., Ltd, Tokyo, Japan, 7Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Public Health, Kyoto, Japan, 8Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka, Japan, 9Miyatake Asthma Clinic, Osaka, Japan and 10Department of Otolaryngology, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan

* To whom correspondence should be addressed at: Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Tel: +81 455039616; Fax: +81 455039615; Email: akahoshi{at}src.riken.jp

Received August 4, 2005; Accepted September 9, 2005

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-{gamma} (IFN-{gamma}), inhibits IgE synthesis and Th2 cell function. As the IFN-{gamma}-inducing cytokines IL-12 and IL-23 utilize IL-12Rß1 as part of their receptors, it is possible that polymorphic variants of the IL-12Rß1 (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-12Rß1 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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