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Human Molecular Genetics Advance Access published online on September 13, 2005
Human Molecular Genetics, 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@oupjournals.org
Received August 4, 2005
Revised September 8, 2005
Accepted September 8, 2005

Article

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

Naomi Takahashi 1, Mitsuteru Akahoshi 2*, Akira Matsuda 3, Kouji Ebe 4, Naoko Inomata 5, Kazuhiko Obara 6, Tomomitsu Hirota 3, Kazuko Nakashima 7, Makiko Shimizu 3, Mayumi Tamari 3, Satoru Doi 8, Akihiko Miyatake 9, Tadao Enomoto 10, Hitoshi Nakashima 11, Zenro Ikezawa 5, and Taro Shirakawa 7

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

* To whom correspondence should be addressed.
Mitsuteru Akahoshi, E-mail: akahoshi{at}src.riken.jp


  Abstract

Atopic dermatitis (AD) is frequently associated with eosinophilia, highly elevated IgE levels, and increased levels of Th2 cytokines in the skin lesions due to infiltrating T cells. IL-12, in combination with IFN-{gamma}, inhibits IgE synthesis and Th2 cell function. As the IFN-{gamma}-inducing cytokines IL-12 and IL-23 utilize IL-12R{beta}1 as part of their receptors, it is possible that polymorphic variants of the IL-12R{beta}1 gene (IL12RB1) 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 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-12R{beta}1 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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