IFNG genotype and sex interact to influence the risk of childhood asthma
IFNG genotype and sex interact to influence the risk of childhood asthma
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DOI：
10.1016/j.jaci.2011.06.016
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发表时间：
2011-09-01
影响因子：
14.2
通讯作者：
Ober, Carole
中科院分区：
文献类型：
--
作者：
Loisel, Dagan A.;Tan, Zheng;Ober, Carole
背景资料：哮喘是一种复杂的疾病，其特征是在发病率、患病率和严重程度上存在性别特异性差异，但对这些性别差异的分子基础知之甚少。目的：为了研究哮喘风险性别差异的遗传结构，我们评估了（1）IFNG基因多态性与儿童期发作哮喘的相关性，包括混合样本和性别特异性样本;（2）方法：在哮喘和过敏性疾病高危儿童出生队列中，研究IFNG遗传多样性对哮喘风险和IFN-γ水平的主要和性别相互作用效应。结果：2个IFNG单核苷酸多态性rs 2069727和rs 2430561在哮喘发病中存在显著的基因型-性别交互作用，且两个多态性之间存在强连锁不平衡。相比之下，10个IFNG单核苷酸多态性中没有一个对哮喘有显著的主效应。观察到的基因型-性别相互作用对哮喘的特点是非加和性，也就是说，杂合子男孩患哮喘的风险最高，杂合子女孩患哮喘的风险最低。这种相互作用对其他哮喘危险因素也有很强的影响，但仅限于在生命的前3年内经历过病毒感染的喘息性疾病的儿童。基因型-性别的相互作用也观察到IFN-γ的反应，LPS在第一年的生活。最后，在一个独立的人口的儿童哮喘cases.Conclusions：这些结果提供了深入了解哮喘的性别差异的遗传基础，并突出性别，基因型和环境因素之间的相互作用在哮喘发病机制的潜在重要性。（J Allergy Clin Immunol 2011;128：524-31.）
Background: Asthma is a complex disease characterized by sex-specific differences in incidence, prevalence, and severity, but little is known about the molecular basis of these sex-based differences.Objective: To investigate the genetic architecture of sex differences in asthma risk, we evaluated (1) associations between polymorphisms in the IFNG gene and childhood-onset asthma in combined and sex-specific samples and (2) interactions between polymorphisms and sex on asthma risk.Methods: Main and sex-interaction effects of IFNG genetic diversity on asthma risk and IFN-gamma levels were examined in a birth cohort of children at high risk for asthma and allergic diseases. Replication of the genetic association was assessed in an independent sample of asthma cases.Results: Significant genotype-sex interactions on asthma were observed for 2 IFNG single nucleotide polymorphisms, rs2069727 and rs2430561, which were in strong linkage disequilibrium with each other. In contrast, none of the 10 IFNG single nucleotide polymorphisms showed significant main effects on asthma. The observed genotype-sex interaction on asthma was characterized by nonadditivity; that is, heterozygous boys had the highest risk for asthma, and heterozygous girls had the lowest risk. The interaction effect was robust to other asthma risk factors but was limited to children who experienced wheezing illnesses with viral infections during the first 3 years of life. Genotype-sex interactions were also observed in the IFN-gamma response to LPS in the first year of life. Finally, the sex-interaction effect was replicated in an independent population of childhood asthma cases.Conclusions: These results provide insight into the genetic basis of sex differences in asthma and highlight the potential importance of interactions among sex, genotype, and environmental factors in asthma pathogenesis. (J Allergy Clin Immunol 2011;128:524-31.)