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, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (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, an SNP in FLJ22447 (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34–1.79, p=6.3×10−9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10−7).
SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and 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).
Abstract
A novel SNP in FLJ22447 is significantly associated with both severe asthma exacerbations in Latino youth and DNA methylation of a cis-CpG in nasal epithelium. This CpG is linked to nasal epithelial expression of a gene implicated in atopic asthma. https://bit.ly/33D9Joc
Footnotes
This article has supplementary material available from erj.ersjournals.com
Author contributions: Q. Yan, E. Forno and J.C. Celedón conceived and designed the study. E.G. Burchard, G.H. Koppelman and J.C. Celedón obtained funding. Q. Yan, E. Herrera-Luis, M. Pino-Yanes and R. Rios conducted the primary analysis and interpreted data. C. Qi, Y-Y. Han, S. Kim, S. Oh, E. Acosta-Pérez, R. Zhang, D. Hu, C. Eng, S. Huntsman, L. Avila, N. Boutaoui, M.M. Cloutier, M.E. Soto-Quiros, C-J. Xu, S.T. Weiss, J. Lasky-Su, M.R. Kiedrowski, C. Figueiredo, J. Bomberger, M.L. Barreto, G. Canino, W. Chen and E.G. Burchard participated in data collection and data analysis. Q. Yan, E. Forno and J.C. Celedón prepared the first draft of the manuscript. All authors reviewed the draft for intellectual content, and approved submission of the final version of the manuscript.
Support statement: This work was supported by grants HL079966, HL117191 and MD011764 from the US National Institutes of Health (NIH) to J.C. Celedón. Q. Yan's contribution was supported by grant HL138098 from the US NIH. E. Forno's contribution was supported by grant HL149693 from the US NIH. The GALA II study was supported by US NIH grants to E.G. Burchard: HL088133, HL004464, HL117004, ES015794, ES24844, TRDRP 24RT 0025, MD006902 and GM007546. M. Pino-Yanes was supported by the Ramón y Cajal Program (RYC-2015-17205) and by grant SAF2017-83417R from the Spanish Ministry of Economy, Industry and Competitiveness. The PIAMA study was supported by The Netherlands Organisation for Health Research and Development; The Netherlands Organisation for Scientific Research; the Lung Foundation of the Netherlands (with methylation and gene expression studies supported by AF 4.1.14.001); The Netherlands Ministry of Spatial Planning, Housing and the Environment; and The Netherlands Ministry of Health, Welfare and Sport. C. Qi was supported by a grant from the China Scholarship Council. Funding information for this article has been deposited with the Crossref Funder Registry.
Conflict of interest: Q. Yan reports grants from National Institutes of Health (K01HL138098), during the conduct of the study.
Conflict of interest: E. Forno has nothing to disclose.
Conflict of interest: E. Herrera-Luis reports grants from the Spanish Ministry of Science, Innovation and Universities (PRE2018-083837), during the conduct of the study.
Conflict of interest: M. 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), and 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: C. Qi has nothing to disclose.
Conflict of interest: R. Rios has nothing to disclose.
Conflict of interest: Y-Y. Han has nothing to disclose.
Conflict of interest: S. Kim has nothing to disclose.
Conflict of interest: S. Oh has nothing to disclose.
Conflict of interest: E. Acosta-Pérez has nothing to disclose.
Conflict of interest: R. Zhang has nothing to disclose.
Conflict of interest: D. Hu has nothing to disclose.
Conflict of interest: C. Eng has nothing to disclose.
Conflict of interest: S. Huntsman has nothing to disclose.
Conflict of interest: L. Avila has nothing to disclose.
Conflict of interest: N. Boutaoui has nothing to disclose.
Conflict of interest: M.M. Cloutier has nothing to disclose.
Conflict of interest: M.E. Soto-Quiros has nothing to disclose.
Conflict of interest: C-J. Xu has nothing to disclose.
Conflict of interest: S.T. Weiss has nothing to disclose.
Conflict of interest: J. Lasky-Su has nothing to disclose.
Conflict of interest: M.R. Kiedrowski has nothing to disclose.
Conflict of interest: C. Figueiredo has nothing to disclose.
Conflict of interest: J. Bomberger has nothing to disclose.
Conflict of interest: M.L. Barreto has nothing to disclose.
Conflict of interest: G. Canino has nothing to disclose.
Conflict of interest: W. Chen has nothing to disclose.
Conflict of interest: G.H. Koppelman reports grants from the Lung Foundation of the Netherlands, during the conduct of the study; grants from Ubbo Emmius Foundation, TETRI Foundation, GSK, Vertex, TEVA, the Lung Foundation of the Netherlands and the European Union H2020 Program, outside the submitted work; and has served on advisory boards to GSK and PURE IMS (fees paid to institution).
Conflict of interest: E.G. Burchard reports grants from National Heart, Lung, and Blood Institute, National Institute of Health, General Medical Sciences, National Institute on Minority Health and Health Disparities, Tobacco-Related Disease Research Program, Food and Drug Administration, and the Sandler Family Foundation, during the conduct of the study.
Conflict of interest: J.C. Celedón 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.
- Received July 15, 2020.
- Accepted September 30, 2020.
- Copyright ©ERS 2021
LIBRARY USERS
Log in through your institution
Purchase access
