Multi-ancestry genome-wide association study of asthma exacerbations.
Multi-ancestry genome-wide association study of asthma exacerbations.
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DOI：
10.1111/pai.13802
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发表时间：
2022-06
影响因子：
4.4
通讯作者：
Pino-Yanes, Maria
中科院分区：
文献类型：
--
作者：
Herrera-Luis, Esther;Ortega, Victor E.;Ampleford, Elizabeth J.;Sio, Yang Yie;Granell, Raquel;de Roos, Emmely;Terzikhan, Natalie;Vergara, Ernesto Elorduy;Hernandez-Pacheco, Natalia;Perez-Garcia, Javier;Martin-Gonzalez, Elena;Lorenzo-Diaz, Fabian;Hashimoto, Simone;Brinkman, Paul;Jorgensen, Andrea L.;Yan, Qi;Forno, Erick;Vijverberg, Susanne J.;Lethem, Ryan;Espuela-Ortiz, Antonio;Gorenjak, Mario;Eng, Celeste;Gonzalez-Perez, Ruperto;Hernandez-Perez, Jose M.;Poza-Guedes, Paloma;Sardon, Olaia;Corcuera, Paula;Hawkins, Greg A.;Marsico, Annalisa;Bahmer, Thomas;Rabe, Klaus F.;Hansen, Gesine;Kopp, Matthias Volkmar;Rios, Raimon;Cruz, Maria Jesus;Gonzalez-Barcala, Francisco-Javier;Maria Olaguibel, Jose;Plaza, Vicente;Quirce, Santiago;Canino, Glorisa;Cloutier, Michelle;Del Pozo, Victoria;Rodriguez-Santana, Jose R.;Korta-Murua, Javier;Villar, Jesus;Potocnik, Uros;Figueiredo, Camila;Kabesch, Michael;Mukhopadhyay, Somnath;Pirmohamed, Munir;Hawcutt, Daniel B.;Melen, Erik;Palmer, Colin N.;Turner, Steve;Maitland-van der Zee, Anke H.;von Mutius, Erika;Celedon, Juan C.;Brusselle, Guy;Chew, Fook Tim;Bleecker, Eugene;Meyers, Deborah;Burchard, Esteban G.;Pino-Yanes, Maria
哮喘恶化是一个严重的公共卫生问题，原因是医疗资源利用率高，工作/学校生产力下降，对生活质量的影响，以及死亡风险。哮喘恶化的遗传基础已经在几个人群中进行了研究，但先前还没有研究对这一特征进行多祖先全基因组关联研究的荟萃分析(META-GWAS)。我们的目标是在不同人群中识别与哮喘恶化相关的常见基因位点，并评估它们在调节DNA甲基化和基因表达方面的功能作用。对4989名欧洲人、2181名拉美裔/拉丁裔、1250名新加坡华人和972名非裔美国人的哮喘恶化进行了Meta-Gwas分析，分析了960万个基因变异。在36,477名欧洲人和1,078名非欧洲人的哮喘患者中，评估了暗示相关变体(p-≤和5×10-−5)的复制情况。在595名西班牙裔/拉丁裔和非裔美国人哮喘患者中，并在公开可用的数据库中评估了对DNA甲基化的功能影响。在电子显微镜下评价其对基因表达的影响。在发现阶段，126个独立变异与哮喘加重有关。两个独立复制的变异体：rs12091010位于血管细胞黏附分子-1/外钙蛋白样糖基转移酶-2(发现：OrC等位基因)和rs943126(发现：orc等位基因−=0.82，p=99.05×10−6和复制：orc等位基因−=0.89，p=35.35×10−3)和rs943126来自泛酸激酶1(发现：orc等位基因=0.85，p=0.010×10−5，复制：orc等位基因=0.89，p=0.30×10−2)。这两个变体都调节它们所在基因的基因表达和全血中邻近基因的DNA甲基化水平。这项多祖先研究揭示了位于参与炎症和宿主防御的基因组区域的哮喘恶化的新的提示调节基因。
Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi‐ancestry meta‐analysis of genome‐wide association studies (meta‐GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. A meta‐GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10−5) were assessed for replication in 36,477 European and 1078 non‐European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. One hundred and twenty‐six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule‐1/exostosin like glycosyltransferase‐2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele) = 0.82, p = 9.05 × 10−6 and replication: ORT allele = 0.89, p = 5.35 × 10−3) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10−5 and replication: ORC allele = 0.89, p = 1.30 × 10−2). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. This multi‐ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.
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影响因子：
12.3
作者：
Jaffe AE;Irizarry RA
通讯作者：
Irizarry RA
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
10.8
作者：
Hortelano, Sonsoles;Lopez-Fontal, Raquel;Luque, Alfonso
通讯作者：
Luque, Alfonso
影响因子：
5.8
作者：
Kamat, Mihir A.;Blackshaw, James A.;Staley, James R.
通讯作者：
Staley, James R.