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- Title
Association of the IL12RB1 promoter polymorphisms with increased risk of atopic dermatitis and other allergic phenotypes.
- Authors
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
- 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.
- Publication
Human Molecular Genetics, 2005, Vol 14, Issue 21, p3149
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddi347