Hirota Tomomitsu, Suzuki Yoichi, Hasegawa Koichi, Obara Kazuhiko, Matsuda Akira, Akahoshi Mitsuteru, Nakashima Kazuko, Cheng Lei, Takahashi Naomi, Shimizu Makiko, Doi Satoru, Fujita Kimie, Enomoto Tadao, Ebisawa Motohiro, Yoshihara Shigemi, Nakamura Yusuke, Kishi Fumio, Shirakawa Taro, Tamari Mayumi
Laboratory for Genetics of Allergic Diseases, Single Nucleotide Polymorphism Research Center, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan.
J Allergy Clin Immunol. 2005 Oct;116(4):789-95. doi: 10.1016/j.jaci.2005.06.010. Epub 2005 Aug 8.
IL-12 is a heterodimeric proinflammatory cytokine that forms a link between innate and adaptive immunity. Although associations between polymorphisms of IL-12B on chromosome 5q31-33 and asthma have been reported, the genetic influences of the polymorphisms and haplotype of IL-12B are unclear.
To examine whether polymorphisms in IL-12B are associated with childhood atopic asthma in a Japanese population.
We identified a total of 13 polymorphisms and characterized the linkage disequilibrium mapping of the gene. Three variants in the promoter and 3' untranslated region were genotyped, and we conducted case-control and case-only association studies between those variants and asthma-related phenotypes (childhood atopic asthma, n = 297; normal controls, n = 555). Haplotype association analysis and functional analysis of these variants were also performed.
3' Untranslated region 10841C > A was significantly associated with the risk of childhood atopic asthma (P = .00062). The -6415 promoter variant, in linkage disequilibrium with the 10841C > A (D' = 0.78 and r2 = 0.61), was also marginally associated with childhood atopic asthma (P = .051). We analyzed the 2-locus haplotype by using these 2 polymorphisms and found a positive association with haplotype CTCTAA-C (-6415 CTCTAA and 10841C; P = .00078). Furthermore, 10841C > A affects the stability of transcripts, and promoter variant -6415GC enhances the transcriptional level of IL-12B.
Our results imply that functional haplotype CTCTAA-C, which affects the instability of transcripts and the lower transcriptional level of IL-12B, has a protective effect in childhood atopic asthma. On the basis of these findings, the IL-12B gene might be involved in the development of atopic asthma through functional genetic polymorphisms.
白细胞介素-12（IL-12）是一种异源二聚体促炎细胞因子，在固有免疫和适应性免疫之间起连接作用。尽管已有报道称5号染色体q31-33上白细胞介素-12B（IL-12B）基因多态性与哮喘有关，但IL-12B基因多态性和单倍型的遗传影响尚不清楚。
研究IL-12B基因多态性是否与日本人群儿童特应性哮喘相关。
我们共鉴定出13个多态性位点，并对该基因的连锁不平衡图谱进行了表征。对启动子和3'非翻译区的3个变异进行基因分型，并对这些变异与哮喘相关表型（儿童特应性哮喘，n = 297；正常对照，n = 555）进行病例对照和单病例关联研究。还进行了这些变异的单倍型关联分析和功能分析。
3'非翻译区10841C>A与儿童特应性哮喘风险显著相关（P = 0.00062）。与10841C>A处于连锁不平衡状态（D' = 0.78，r2 = 0.61）的-6415启动子变异也与儿童特应性哮喘存在边缘关联（P = 0.051）。我们利用这两个多态性位点分析了两位点单倍型，发现与单倍型CTCTAA-C呈正相关（-6415 CTCTAA和10841C；P = 0.00078）。此外，10841C>A影响转录本的稳定性，启动子变异-6415GC可提高IL-12B的转录水平。
我们的结果表明，影响转录本不稳定性和IL-12B转录水平降低的功能性单倍型CTCTAA-C对儿童特应性哮喘具有保护作用。基于这些发现，IL-12B基因可能通过功能性基因多态性参与特应性哮喘的发生发展。
Zotero 插件