Abstract
Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups. To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians, and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus (mQTL), expression quantitative trait locus (eQTL), and expression quantitative trait methylation (eQTM) analyses to assess whether the top SNP in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents. In the meta-analysis of GWAS, a SNP inFLJ22447(rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbations (95% confidence interval=1.34 to 1.79, p=6.3×10−9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at theFLJ22447locus, which was in turn associated with increased expression ofKCNJ2-AS1in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10−7). Thus, SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG inFLJ22447and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents (KCNJ2-AS1).
Footnotes
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Conflict of interest: Dr. Yan reports grants from National Institutes of Health, during the conduct of the study;.
Conflict of interest: Dr. Fomo has nothing to disclose.
Conflict of interest: Esther Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation, and Universities (PRE2018-083837), during the conduct of the study.
Conflict of interest: Dr. Pino-Yanes reports grants from Spanish Ministry of Economy, Industry, and Competitiveness, the State Research Agency and the European Regional Development Funds from the European Union (MINECO/AEI/FEDER, UE, SAF2017-83417R), grants from Spanish Ministry of Economy, Industry, and Competitiveness (Ramón y Cajal grant RYC-2015-17205), during the conduct of the study.
Conflict of interest: Dr. Qi has nothing to disclose.
Conflict of interest: Dr. Rios has nothing to disclose.
Conflict of interest: Dr. Han has nothing to disclose.
Conflict of interest: Dr. Kim has nothing to disclose.
Conflict of interest: Dr. Oh has nothing to disclose.
Conflict of interest: Dr. Acosta-Pérez has nothing to disclose.
利益冲突:张博士称号g to disclose.
Conflict of interest: Dr. Hu has nothing to disclose.
Conflict of interest: Dr. Eng has nothing to disclose.
Conflict of interest: Dr. Huntsman has nothing to disclose.
Conflict of interest: Dr. Avila has nothing to disclose.
Conflict of interest: Dr. Boutaoul has nothing to disclose.
Conflict of interest: Dr. Cloutier has nothing to disclose.
Conflict of interest: Dr. Soto-Quiros has nothing to disclose.
Conflict of interest: Dr. Xu has nothing to disclose.
Conflict of interest: Dr. Weiss has nothing to disclose.
Conflict of interest: Dr. Lasky-Su has nothing to disclose.
Conflict of interest: Dr. Kiedrowski has nothing to disclose.
Conflict of interest: Dr. Figueiredo has nothing to disclose.
Conflict of interest: Dr. Bomberger has nothing to disclose.
Conflict of interest: Dr. Barreto has nothing to disclose.
Conflict of interest: Dr. Canino has nothing to disclose.
Conflict of interest: Dr. Chen has nothing to disclose.
Conflict of interest: Gerard Koppelman served on advisory boards to GSK and PURE IMS (Money to Institution).
Conflict of interest: Dr. Burchard reports grants from National Institute of Health, Lung, Blood Institute, grants from National Institute of Health, General Medical Sciences, grants from National Institute on Minority Health and Health Disparities, grants from the Tobacco-Related Disease Research Program, grants from FOOD AND DRUG ADMINISTRATION, grants from Sandler Family Foundation, during the conduct of the study.
Conflict of interest: Dr. Celedo has received research materials from GSK and Merck (inhaled steroids) and Pharmavite (vitamin D and placebo capsules), in order to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work.
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- ReceivedJuly 15, 2020.
- AcceptedSeptember 30, 2020.
- Copyright ©ERS 2020