Identification of Four Novel Loci in Asthma in European American and African American Populations
Identification of Four Novel Loci in Asthma in European American and African American Populations
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DOI：
10.1164/rccm.201604-0861oc
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发表时间：
2017-02-15
影响因子：
24.7
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
--
作者：
Almoguera, Berta;Vazquez, Lyam;Hakonarson, Hakon
基本原理：尽管哮喘的遗传结构的知识有了很大的进步，但不同人群之间的负担差异的具体因素仍然没有被发现。目的：确定欧洲裔美国人和非洲裔美国人人群中哮喘的其他遗传易感因素。开发了一种挖掘电子病历的表型分型算法，并验证了从电子病历中招募哮喘病例和对照受试者Genomics网络在具有欧洲裔美国人和非洲裔美国人血统的儿童和成人哮喘病例以及对照受试者中进行全基因组关联分析，然后进行荟萃分析。名义上显着的结果进行了重新分析条件过敏status.Measurements和主要结果：该算法的验证产生了平均95.8%的阳性预测值的情况下，对照组。该算法纳入了21，644例受试者（65.83%欧洲裔美国人和34.17%非洲裔美国人）。在荟萃分析后，我们确定了四种新的人群特异性与哮喘的相关性：欧洲裔美国人中的6p21.31、9p21.2和10q21.3位点，以及非洲裔美国人中的PTGES基因。编码TIE 2的9p21.2处的TEK已被证明参与哮喘气道壁的重塑，并且在过敏调节后这种关联仍然显著。PTGES，它编码的前列腺素E合成酶，也被链接到哮喘，其中缺乏前列腺素E-2的合成已与气道remodeling.Conclusions：这项研究增加了对哮喘的遗传结构的理解在欧洲裔美国人和非洲裔美国人，并加强了需要研究不同种族背景的人群，以确定共享和独特的遗传预测哮喘。
Rationale: Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered.Objectives: To identify additional genetic susceptibility factors of asthma in European American and African American populations.Methods: A phenotyping algorithm mining electronic medical records was developed and validated to recruit cases with asthma and control subjects from the Electronic Medical Records and Genomics network. Genome-wide association analyses were performed in pediatric and adult asthma cases and control subjects with European American and African American ancestry followed by metaanalysis. Nominally significant results were reanalyzed conditioning on allergy status.Measurements and Main Results: The validation of the algorithm yielded an average of 95.8% positive predictive values for both cases and control subjects. The algorithm accrued 21,644 subjects (65.83% European American and 34.17% African American). We identified four novel population-specific associations with asthma after metaanalyses: loci 6p21.31, 9p21.2, and 10q21.3 in the European American population, and the PTGES gene in African Americans. TEK at 9p21.2, which encodes TIE2, has been shown to be involved in remodeling the airway wall in asthma, and the association remained significant after conditioning by allergy. PTGES, which encodes the prostaglandin E synthase, has also been linked to asthma, where deficient Prostaglandin E-2 synthesis has been associated with airway remodeling.Conclusions: This study adds to understanding of the genetic architecture of asthma in European Americans and African Americans and reinforces the need to study populations of diverse ethnic backgrounds to identify shared and unique genetic predictors of asthma.