title: An epigenome-wide association study of total serum immunoglobulin E concentration.
abstract: Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever and allergic asthma. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations--with a meta-analysis false discovery rate less than 10(-4)--between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.
authors.affiliation: Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, MA 02115.
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
authors.forename: Saffron A G
authors.initials: SAG
authors.lastname: Willis-Owen
authors.affiliation: Université du Québec à Chicoutimi, Saguenay, Québec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
authors.forename: Kenny C C
authors.initials: KCC
authors.lastname: Wong
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, SA2 8PP, UK.
authors.forename: Gwyneth A
authors.initials: GA
authors.lastname: Davies
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario Canada, M5G 0A3.|Departments of Medical Biophysics and Molecular Genetics, University of Toronto, Canada ON M5S 1A1.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
authors.forename: Aristea
authors.initials: A
authors.lastname: Binia
authors.affiliation: Institute of Life Science, College of Medicine, Swansea University, SA2 8PP, UK.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Hopkin
authors.affiliation: University of Colorado School of Medicine and National Jewish Health, Denver, CO 80206.
authors.forename: Ivana V
authors.initials: IV
authors.lastname: Yang
authors.affiliation: Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.affiliation: Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.affiliation: Jewish General Hospital and Lady Davis Research Institute, Montréal, Canada H3T 1E2.
authors.forename: Marie
authors.initials: M
authors.lastname: Hudson
authors.affiliation: Department of Medical Sciences, SciLifeLab, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.affiliation: Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Canada.|Department of Medical Genetics, McGill University Health Centre, Montréal, Canada.
authors.forename: Tomi M
authors.initials: TM
authors.lastname: Pastinen
authors.affiliation: University of Colorado School of Medicine and National Jewish Health, Denver, CO 80206.
authors.forename: David A
authors.initials: DA
authors.lastname: Schwartz
authors.affiliation: Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: G Mark
authors.initials: GM
authors.lastname: Lathrop
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Moffatt
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
authors.forename: William O C M
authors.initials: WOCM
authors.lastname: Cookson
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000097:blood / Q000235:genetics; D002648:Child; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood*; D018836:Inflammation Mediators; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: D018836:Inflammation Mediators; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D007073:Immunoglobulin E