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-gamma (IFN-gamma), inhibits IgE synthesis and Th2 cell function. As the IFN-gamma-inducing cytokines IL-12 and IL-23 utilize IL-12Rbeta1 as part of their receptors, it is possible that polymorphic variants of the IL-12Rbeta1 (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-12Rbeta1 expression may lead to increased Th2 cytokine production in the skin and contribute to the development of AD and other subsequent allergic diseases.
authors.affiliation: Laboratory of Genetics of Allergic Diseases, SNP Research Center, RIKEN, Kanagawa, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Takahashi
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Akahoshi
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Kouji
authors.initials: K
authors.lastname: Ebe
authors.forename: Naoko
authors.initials: N
authors.lastname: Inomata
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Obara
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hirota
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamari
authors.forename: Satoru
authors.initials: S
authors.lastname: Doi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyatake
authors.forename: Tadao
authors.initials: T
authors.lastname: Enomoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Zenro
authors.initials: Z
authors.lastname: Ikezawa
authors.forename: Taro
authors.initials: T
authors.lastname: Shirakawa
mesh_terms: D000293:Adolescent; D000328:Adult; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D003876:Dermatitis, Atopic / Q000235:genetics*; D005260:Female; D040461:Gene Components; D005786:Gene Expression Regulation / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007564:Japan; D008156:Luciferases; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D053707:Receptors, Interleukin-12; D017422:Sequence Analysis, DNA; D018418:Th2 Cells / Q000378:metabolism
chemical_list: D016207:Cytokines; D017931:DNA Primers; C508438:IL12RB1 protein, human; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D007073:Immunoglobulin E; D008156:Luciferases