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A Genome-wide Study of DNA Methylation in Nasal Epithelium and Atopy and Atopic Asthma in Children

20 Pages Posted: 6 Nov 2018

See all articles by Erick Forno

Erick Forno

University of Pittsburgh - Department of Pediatrics

Ting Wang

University of Pittsburgh - School of Medicine

Cancan Qi

Beatrix Children’s Hospital

Qi Yan

University of Pittsburgh - Department of Pediatrics

Cheng-Jian Xu

Beatrix Children’s Hospital

Nadia boutaoui

University of Pittsburgh - Department of Pediatrics

Yueh-Ying Han

University of Pittsburgh - Department of Pediatrics

Daniel Weeks

University of Pittsburgh - Graduate School of Public Health

Yale Jiang

University of Pittsburgh - Department of Pediatrics

Franziska Rosser

University of Pittsburgh - Department of Pediatrics

Judith Vonk

University of Pittsburgh - Graduate School of Public Health

Sharon Brouwer

University of Pittsburgh - Graduate School of Public Health

Edna Acosta-Perez

Behavioral Sciences Research Institute

Angel Colon-Semidey

University of Puerto Rico Medical Sciences Campus

Maria Alvarez

University of Puerto Rico Medical Sciences Campus

Glorisa Canino

Behavioral Sciences Research Institute

Gerard Koppelman

University of Pittsburgh - Graduate School of Public Health

Wei Chen

University of Pittsburgh - Department of Pediatrics

Juan C. Celedon

University of Pittsburgh - Department of Pediatrics

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Abstract

BACKGROUND: Up to 10-12% of U.S. children and adolescents report respiratory or skin allergies. Epigenetic mechanisms may alter the airway epithelial barrier and ultimately lead to atopic diseases. Here we aim to identify DNA methylation profiles that are associated with - and accurately classify - atopy and atopic asthma in school-aged children.

METHODS: We conducted an epigenome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 482 Puerto Rican children. Significant methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort including 72 predominantly African American children, and in another cohort including 432 children of European descent. Next, we tested nasal methylation-based classification models of atopy or atopic asthma in all cohorts.

FINDINGS: DNA methylation profiles were markedly different between subjects with and without atopy. After adjustment for covariates and multiple testing, we found 8,664 differentially methylated CpGs by atopy, with P-values ranging from 9·58*e-17 to 2·18*e-22 for the top 30 CpGs. These CpGs are in or near genes relevant to epithelial barrier function, including CDHR3 (cadherin-related family member 3) and CDH26 (cadherin 26), and in other biologically plausible genes like FBXL7 (F-box and leucine-rich repeat protein 7), NTRK1 (neurotrophic receptor tyrosine kinase 1), and SLC9A3 (solute carrier family 9 member A3). Moreover, 28 of the top 30 CpGs replicated in both cohorts. Nasal methylation-based classification models of atopy and atopic asthma performed well in the Puerto Rico cohort (area under the curve=0·93-0·94 and accuracy=85%-88%) and in both replication cohorts (AUC=0·74-0·92, accuracy=68%-82%).

INTERPRETATION: We have identified methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation profile that classified children by atopy or atopic asthma. This panel performed well in three independent cohorts from different ethnic/racial backgrounds.

Funding: This study was supported by grants HL079966, HL117191, and MD011764 (PI: Celedón JC) from the National Heart, Lung, and Blood Institute (NHLBI) of the U.S. National Institutes of Health (NIH). Dr. Forno’s contribution was supported by NIH grant HL125666. Dr. Celedón’s contribution was additionally supported by The Heinz Endowments. Research operations at the University of Puerto Rico were additionally supported by grant U54MD007587 from the National Institute on Minority Health and Health Disparities (NIMHD) and the National Institute of Allergy and Infectious Diseases (NIAID) of the U.S. NIH. PIAMA was supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Lung Foundation (with methylation 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. Dr. Qi is supported by a grant from the China Scholarship Council.

Declaration of Interest: Dr. Celedón has received research materials from Merck, GSK and Pharmavite, to provide medications free of cost to participants in NIH-funded studies, unrelated to the current work. The other authors report no conflicts of interest.

Ethical Approval: The study was approved by the institutional review boards of the University of Puerto Rico (San Juan, PR) and the University of Pittsburgh (Pittsburgh, PA).

Suggested Citation

Forno, Erick and Wang, Ting and Qi, Cancan and Yan, Qi and Xu, Cheng-Jian and boutaoui, Nadia and Han, Yueh-Ying and Weeks, Daniel and Jiang, Yale and Rosser, Franziska and Vonk, Judith and Brouwer, Sharon and Acosta-Perez, Edna and Colon-Semidey, Angel and Alvarez, Maria and Canino, Glorisa and Koppelman, Gerard and Chen, Wei and Celedón, Juan, A Genome-wide Study of DNA Methylation in Nasal Epithelium and Atopy and Atopic Asthma in Children (June 18, 2018). Available at SSRN: https://ssrn.com/abstract=3276045

Erick Forno (Contact Author)

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

Ting Wang

University of Pittsburgh - School of Medicine ( email )

200 Meyran Avenue
Suite 200
Pittsburgh, PA 15213
United States

Cancan Qi

Beatrix Children’s Hospital ( email )

Hanzeplein 1
9713 GZ Groningen
Netherlands

Qi Yan

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

Cheng-Jian Xu

Beatrix Children’s Hospital ( email )

Hanzeplein 1
9713 GZ Groningen
Netherlands

Nadia Boutaoui

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

Yueh-Ying Han

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

Daniel Weeks

University of Pittsburgh - Graduate School of Public Health ( email )

Pittsburgh, PA 15260-0001
United States

Yale Jiang

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

Franziska Rosser

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

Judith Vonk

University of Pittsburgh - Graduate School of Public Health ( email )

Pittsburgh, PA 15260-0001
United States

Sharon Brouwer

University of Pittsburgh - Graduate School of Public Health ( email )

Pittsburgh, PA 15260-0001
United States

Edna Acosta-Perez

Behavioral Sciences Research Institute ( email )

San Juan
Puerto Rico

Angel Colon-Semidey

University of Puerto Rico Medical Sciences Campus ( email )

P. O. Box 365067
San Juan, 00936-5067
Puerto Rico

Maria Alvarez

University of Puerto Rico Medical Sciences Campus ( email )

P. O. Box 365067
San Juan, 00936-5067
Puerto Rico

Glorisa Canino

Behavioral Sciences Research Institute ( email )

San Juan
Puerto Rico

Gerard Koppelman

University of Pittsburgh - Graduate School of Public Health ( email )

Pittsburgh, PA 15260-0001
United States

Wei Chen

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

Juan Celedón

University of Pittsburgh - Department of Pediatrics ( email )

Pittsburgh, PA 15244
United States

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