Epigenome-wide association study of asthma and wheeze characterizes loci within HK1

• Type of Material: Article
• Authors: Todd Everson, Emory University; Hongmei Zhang, University of Memphis; Gabrielle A. Lockett, University of Southampton; Akhilesh Kaushal, Baylor College of Medicine; Melinda Forthofer, University of South Carolina; Susan L. Ewart, Michigan State University; Kimberley Burrows, University of Bristol; Caroline L. Relton, University of Bristol; Gemma C. Sharp, University of Bristol; A. John Henderson, University of Bristol; Veeresh K. Patil, St Mary’s Hospital; Faisal I. Rezwa, University of Southampton; S. Hasan Arshad, University of Southampton; John W. Holloway, University of Southampton; Wilfried Karmau, University of Memphis
• Language: English
• Date: 2019-07-24
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: Copyright © The Author(s) 2019
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13223-019-0356-z
• Title of Journal or Parent Work: Allergy, Asthma and Clinical Immunology
• ISSN: 1710-1484
• Volume: 15
• Start Page: 43
• End Page: 43
• Grant/Funding Information: The IOW portion of this work was supported by the National Institute of Health under award numbers R01 AI091905 and R01HL132321 (PI: Wilfried Karmaus) and R01AI121226 (MPI: Hongmei Zhang, John Holloway).; We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z) for the generation of the IOW methylation data.; The UK Medical Research Council and the Wellcome Trust (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC.; The Accessible Resource for Integrated Epigenomics Studies (ARIES) was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1).; This work was supported by the Medical Research Council Integrative Epidemiology Unit; and the University of Bristol (MC_UU_12013_2).; The 10-year follow-up of this study was funded by the National Asthma Campaign, UK (Grant No 364); and the 18-year follow-up by NIH/NHLBI R01 HL082925-01 (PI: S. Hasan Arshad).
• Keywords: Science & Technology; Methylation; ALSPAC; CHILDHOOD ASTHMA; Isle of Wight; Immunology; BLOOD-CELL; HK1; CONSTITUTIVE NEUTROPHIL APOPTOSIS; Hexokinase-1; DNA METHYLATION; ATOPY; Life Sciences & Biomedicine; TUMOR-NECROSIS-FACTOR; Infant wheeze; ARIES; Allergy; Expression; Asthma; BIRTH
• Research Categories: Health Sciences, Epidemiology; Environmental Sciences; Health Sciences, Immunology

Abstract

Background: To identify novel epigenetic markers of adolescent asthma and replicate findings in an independent cohort, then explore whether such markers are detectable at birth, predictive of early-life wheeze, and associated with gene expression in cord blood. Methods: We performed epigenome-wide screening with recursive random forest feature selection and internal validation in the IOW birth cohort. We then tested whether we could replicate these findings in the independent cohort ALSPAC and followed-up our top finding with children of the IOW cohort. Results: We identified 10 CpG sites associated with adolescent asthma at a 5% false discovery rate (IOW, n = 370), five of which exhibited evidence of associations in the replication study (ALSPAC, n = 720). One site, cg16658191, within HK1 displayed particularly strong associations after cellular heterogeneity adjustments in both cohorts (ORIOW = 0.17, 95% CI 0.04-0.57) (ORALSPAC = 0.57, 95% CI 0.38-0.87). Additionally, higher expression of HK1 (OR = 3.81, 95% CI 1.41-11.77) in cord blood was predictive of wheezing in infancy (n = 82). Conclusion: We identified novel associations between asthma and wheeze with methylation at cg16658191 and the expression of HK1, which may serve as markers of, predictors of, and potentially etiologic factors involved in asthma and early life wheeze.