An epigenome-wide association study of total serum immunoglobulin E concentration

• Published in: Nature (London) 2015-04, Vol.520 (7549), p.670-674
• Main Authors: Liang, Liming, Willis-Owen, Saffron A. G., Laprise, Catherine, Wong, Kenny C. C., Davies, Gwyneth A., Hudson, Thomas J., Binia, Aristea, Hopkin, Julian M., Yang, Ivana V., Grundberg, Elin, Busche, Stephan, Hudson, Marie, Rönnblom, Lars, Pastinen, Tomi M., Schwartz, David A., Lathrop, G. Mark, Moffatt, Miriam F., Cookson, William O. C. M.
• Format: Article
• Language: English
• Subjects: 45; 45/43; 631/208/176/1988; Adolescent; Adult; Allergies; Asthma; Asthma - blood; Asthma - genetics; Child; CpG Islands - genetics; DNA methylation; DNA Methylation - genetics; Eosinophils - cytology; Eosinophils - metabolism; Epigenesis, Genetic - genetics; Epigenetics; Female; Gene expression; Genetic aspects; Genetic Association Studies; Genome, Human - genetics; Genome-wide association studies; Genomes; Hay fever; Humanities and Social Sciences; Humans; Immunoglobulin E; Immunoglobulin E - blood; Immunoglobulins; Inflammation Mediators; letter; Male; Methylation; Middle Aged; Mitochondrial Proteins - genetics; multidisciplinary; Pedigree; Polymorphism, Single Nucleotide - genetics; Proteins; Science; Studies; Systematic review; Transcription factors; Transcription Factors - genetics; Young Adult
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature14125

A survey of epigenetic associations between serum immunoglobulin E concentrations indicating allergy and methylation at CpG islands in families and a population sample has revealed associations at 36 loci that harbour genes encoding proteins including eosinophil products and phospholipid inflammatory mediators. IgE blocker targets identified Drugs that block immunoglobulin E (IgE) are widely used to treat asthma, hay fever and allergic asthma, but genetic association studies have failed to identify the pathways underlying the pathways that regulate IgE's role in mediating the allergic state. Using DNA from peripheral blood leukocytes, William Cookson and colleagues surveyed families for epigenetic associations between serum IgE concentrations and methylation at CpG islands genome-wide. They identified associations between IgE and low methylation at 36 loci that harbour genes encoding proteins including eosinophil products and phospholipid inflammatory mediators. The three most-associated loci accounted for 13% of IgE variation in the primary subject panel. The study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases. Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever 1 and allergic asthma 1 , 2 . Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation 3 , 4 , 5 , 6 . 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 3 , 4 . T