| Description | BARRETO, Maurício Lima. Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. “Documento protegido em parceria ou por autor vinculado à Fiocruz, mas não consta à informação no documento”. 1Division of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA. 2Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Santa Cruz de Tenerife, Spain. 3CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. 4University of Groningen, University Medical Center Groningen, Dept. of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children’s Hospital, and 5University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands. 6Instituto de Ciências da Saúde, Universidade Federal da Bahia, Vale do Canela, Salvador, Bahia, Brazil. 7Department of Medicine, University of California San Francisco, San Francisco, CA, USA. 8Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto Rico. 9Department of Pediatrics, Hospital Nacional de Niños, San José, Costa Rica. 10Department of Pediatrics, University of Connecticut, Farmington, CT, USA. 11CiiM and TWINCORE, joint ventures between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany. 12Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands. 13Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 14Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA. 15Instituto de Saúde Coletiva, Federal University of Bahia, Salvador, Brazil. | pt_BR |
| Sponsorship | This work was supported by grants HL079966, HL117191, and MD011764 from the U.S. National Institutes of Health (NIH) to J.C.C. Dr. Yan’s contribution was supported by grant HL138098 from the U.S. NIH. Dr. Forno’s contribution was supported by grant HL149693 from the U.S. NIH. The GALA II study was supported by U.S. NIH grants to E.G.B:HL088133, HL004464, HL117004, ES015794, ES24844, TRDRP 24RT 0025, MD006902, and GM007546. M.P.Y. 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 Organization for Health Research and Development; The Netherlands Organization 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.Q. was supported by a grant from the China Scholarship Council. | |
| 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 4,010 Latino youth with asthma in four independent cohorts, including 1,693 Puerto Ricans, 1,019 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 in FLJ22447 (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 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 x 10-7). Thus, 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). | en_US |
