Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations
Genome-wide association study reveals class I MHC-restricted T cell-associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations
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DOI：
10.1016/j.jaci.2011.09.034
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发表时间：
2012-02-01
影响因子：
14.2
通讯作者：
Weiss, Scott T.
中科院分区：
文献类型：
--
作者：
Du, Rose;Litonjua, Augusto A.;Weiss, Scott T.
背景资料：最近的研究表明，维生素D缺乏会增加哮喘的发生和严重程度，维生素D受体基因的变异与哮喘易感性有关。目的：我们试图找到可能与维生素D水平相互作用影响哮喘急性发作风险的遗传因素。我们进行了一项基因-维生素D相互作用对哮喘急性发作的全基因组研究，使用基于人群和家庭的方法，基于儿童哮喘管理项目的403名受试者和三人组的方法。23个多态性与显着的相互作用进行了研究，在584名儿童从Costa Rican cohol.Results的复制分析：我们确定了3个常见的变异在I类MHC限制性T细胞相关分子基因（CRTAM），与哮喘急性发作的基础上存在的低循环维生素D水平的增加率。这些结果在第二个独立人群中得到了重复（未校正的联合相互作用，P = 0.00028 - 0.00097;联合优势比，3.28-5.38）。一种变体rs 2272094是CRTAM的非同义编码多态性。对细胞系的功能研究证实了维生素D和rs 2272094对CRTAM表达的相互作用。CRTAM在活化的人CD 8（+）和自然杀伤T细胞中高度表达，这两者都与哮喘患者有牵连。结论：研究结果突出了一个重要的基因-环境相互作用，阐明了维生素D和CD 8（+）和自然杀伤T细胞在哮喘急性发作中的作用，在一个全基因组基因-环境相互作用研究中，已在一个独立的人群中重复。结果表明，在高危哮喘患者亚群中维持足够的维生素D水平具有潜在的重要性。（J Allergy Clin Immunol 2012;129：368-73.）
Background: It has recently been shown that vitamin D deficiency can increase asthma development and severity and that variations in vitamin D receptor genes are associated with asthma susceptibility.Objective: We sought to find genetic factors that might interact with vitamin D levels to affect the risk of asthma exacerbation.Methods: We conducted a genome-wide study of gene-vitamin D interaction on asthma exacerbations using population-based and family-based approaches on 403 subjects and trios from the Childhood Asthma Management Program. Twenty-three polymorphisms with significant interactions were studied in a replication analysis in 584 children from a Costa Rican cohort.Results: We identified 3 common variants in the class I MHC-restricted T cell-associated molecule gene (CRTAM) that were associated with an increased rate of asthma exacerbations based on the presence of a low circulating vitamin D level. These results were replicated in a second independent population (unadjusted combined interaction, P = .00028-.00097; combined odds ratio, 3.28-5.38). One variant, rs2272094, is a nonsynonymous coding polymorphism of CRTAM. Functional studies on cell lines confirmed the interaction of vitamin D and rs2272094 on CRTAM expression. CRTAM is highly expressed in activated human CD8(+) and natural killer T cells, both of which have been implicated in asthmatic patients.Conclusion: The findings highlight an important gene-environment interaction that elucidates the role of vitamin D and CD8(+) and natural killer T cells in asthma exacerbation in a genome-wide gene-environment interaction study that has been replicated in an independent population. The results suggest the potential importance of maintaining adequate vitamin D levels in subsets of high-risk asthmatic patients. (J Allergy Clin Immunol 2012;129:368-73.)