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 fever1 and allergic asthma1,2. Genetic association

studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation3,4,5,6. 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 studies3,4. This study

identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases. Access through your institution Buy or subscribe This is a preview of subscription

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ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS EXOME VARIANTS ASSOCIATED WITH ASTHMA AND

ALLERGY Article Open access 05 December 2022 EPIGENOMIC AND PROTEOMIC ANALYSES PROVIDE INSIGHTS INTO EARLY-LIFE IMMUNE REGULATION AND ASTHMA DEVELOPMENT IN INFANTS Article Open access 15

April 2025 A WHOLE GENOME SEQUENCING STUDY OF MODERATE TO SEVERE ASTHMA IDENTIFIES A LUNG FUNCTION LOCUS ASSOCIATED WITH ASTHMA RISK Article Open access 02 April 2022 REFERENCES * Holgate,

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27, 1133–1163 (2008) Article  MathSciNet  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by the Freemasons’ Grand Charity. The study was also funded by the

Wellcome Trust under grants WT 077959 and WT096964, the UK Medical Research Council, a grant to G.M.L. from Génome Québec, le Ministère de l’Enseignement supérieur, de la Recherche, de la

Science et de la Technologie (MESRST), Québec and McGill University, and the National Institutes of Health R01s HL101251-01 and P01-ES18181. M.F.M. and W.O.C.M.C. are Joint Wellcome Trust

Senior Investigators, W.O.C.M.C. is a National Institute for Health Research Senior Investigator and C.L. is the Chairholder of the Canada Research Chair on Genetic Determinants in Asthma.

We thank A.-M. Madore and V. T. Vaillancourt for the eosinophil isolation and M. Laviolette and N. Flamand for their advice on this technique. AUTHOR INFORMATION Author notes * Saffron A. G.

Willis-Owen and Catherine Laprise: These authors contributed equally to this work. * G. Mark Lathrop, Miriam F. Moffatt and William O. C. M. Cookson: These authors jointly supervised this

work. AUTHORS AND AFFILIATIONS * Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, 02115, Massachusetts, USA Liming Liang * National Heart and Lung

Institute, Imperial College, London SW3 6LY, UK, Saffron A. G. Willis-Owen, Kenny C. C. Wong, Aristea Binia, Miriam F. Moffatt & William O. C. M. Cookson * Université du Québec à

Chicoutimi, Saguenay, Québec G7H 2B1, Canada, Catherine Laprise * Institute of Life Science, College of Medicine, Swansea University, Swansea SA2 8PP, UK, Gwyneth A. Davies & Julian M.

Hopkin * Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada, Thomas J. Hudson * Departments of Medical Biophysics and Molecular Genetics, University of Toronto, Ontario

M5S 1A1, Canada, Thomas J. Hudson * University of Colorado School of Medicine and National Jewish Health, Denver, 80206, Colorado, USA Ivana V. Yang & David A. Schwartz * Department of

Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal H3A 1B1, Canada, Elin Grundberg, Stephan Busche, Tomi M. Pastinen & G. Mark Lathrop * Jewish General

Hospital and Lady Davis Research Institute, Montréal H3T 1E2, Canada, Marie Hudson * Department of Medical Sciences, SciLifeLab, Uppsala University, Uppsala SE-751 44, Sweden, Lars Rönnblom

* Department of Medical Genetics, McGill University Health Centre, Montréal H3H 1P3, Canada, Tomi M. Pastinen Authors * Liming Liang View author publications You can also search for this

author inPubMed Google Scholar * Saffron A. G. Willis-Owen View author publications You can also search for this author inPubMed Google Scholar * Catherine Laprise View author publications

You can also search for this author inPubMed Google Scholar * Kenny C. C. Wong View author publications You can also search for this author inPubMed Google Scholar * Gwyneth A. Davies View

author publications You can also search for this author inPubMed Google Scholar * Thomas J. Hudson View author publications You can also search for this author inPubMed Google Scholar *

Aristea Binia View author publications You can also search for this author inPubMed Google Scholar * Julian M. Hopkin View author publications You can also search for this author inPubMed 

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author inPubMed Google Scholar * Stephan Busche View author publications You can also search for this author inPubMed Google Scholar * Marie Hudson View author publications You can also

search for this author inPubMed Google Scholar * Lars Rönnblom View author publications You can also search for this author inPubMed Google Scholar * Tomi M. Pastinen View author

publications You can also search for this author inPubMed Google Scholar * David A. Schwartz View author publications You can also search for this author inPubMed Google Scholar * G. Mark

Lathrop View author publications You can also search for this author inPubMed Google Scholar * Miriam F. Moffatt View author publications You can also search for this author inPubMed Google

Scholar * William O. C. M. Cookson View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.A.G.W.-O., W.O.C.M.C., G.M.L. and M.F.M. planned the

initial study. S.A.G.W.-O., A.B. and K.C.C.W. performed measurements of methylation status. L.L. and W.O.C.M.C. led statistical analyses of the data with S.A.G.W.-O. and G.M.L.: most

analyses were carried out by L.L. G.M.L. and T.M.P. led discussions on replication strategy, methylation assays and cell-specific methylation, with contributions from M.F.M., D.A.S. and

I.V.Y. E.G. validated Ilumina probes with bisulphite sequencing. C.L. led studies of SLSJ families with T.J.H., and G.A.D. and J.M.H. led studies of the PAPA subjects. C.L. led studies of

isolated eosinophils. M.H., L.R. and S.B. recruited subjects and studied lymphocyte subsets. W.O.C.M.C. wrote the first draft of the paper. All authors contributed to the interpretation of

the results and the writing of the paper. CORRESPONDING AUTHOR Correspondence to William O. C. M. Cookson. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial

interests. EXTENDED DATA FIGURES AND TABLES EXTENDED DATA FIGURE 1 CONCORDANCE IN METHYLATION STATUS AT IGE-ASSOCIATED LOCI WHEN COMPARING WHOLE-GENOME BISULPHITE SEQUENCING WITH THE

ILLUMINA PLATFORM. These results were produced by us (E.G. and T.M.P.) at the Genome Québec Innovation Centre. The figures show a comparison between IgE-associated CpG probes using Illumina

450K (_x_-axis) and whole-genome bisulphite sequencing (WGBS) (_y_-axis) platforms for two samples (left and right panels) with 20-fold sequence coverage. The results show a high _R_2

between platforms (0.76 and 0.73). The median of the correlation coefficients for our IgE-associated loci across 30 different samples (using WGBS at various depths) was _R_2 = 0.76. This can

be compared with the global assessment of all overlapping 450K sites, which is _R_2 = 0.81. EXTENDED DATA FIGURE 2 DISTRIBUTION OF METHYLATION STATUS AT IGE-ASSOCIATED LOCI IN ISOLATED

LEUKOCYTE SUBSETS. A–L, The figure shows the distribution of methylation in PBL subsets at the most strongly IgE-associated loci. CpG methylation was measured by the Illumina Infinium 450K

platform. Boxplots show means and interquartile ranges. A, C, E, G, I, K, Results from publically available data derived from six healthy controls21. Lower levels of methylation with wider

variation are observed in eosinophils when compared to whole blood (WB) and subsets comprising CD14+ monocytes (CD14+M); CD19+ B cells (CD19+B); CD4+ T cells (CD4+T); CD56+ natural killer

cells (CD56+NK); CD8+ T cells (CD8+T); granulocytes (Gran); neutrophils (Neu) and peripheral blood mononuclear cells (PBMCs). B, D, F, H, J, L, Results from cells isolated and analysed by us

at the McGill University Genome Québec Innovation Centre (MUGQIC). Eosinophils (Eos) (from 24 subjects in the SLSJ panel) also show lower levels of methylation with wider variation compared

to whole blood (22 SLSJ subjects), and to subsets including B cells (BC; 9 control subjects), monocytes (Mono; 76 control subjects) and T cells (TC; 74 control subjects). KW Test,

Kruskal–Wallis one-way analysis of variance. EXTENDED DATA FIGURE 3 POWER ESTIMATIONS TO DETECT EOSINOPHIL-SPECIFIC EFFECTS IN DNA FROM PBL. The figure shows that our original MRCA data set

(green line) and our combined data set (blue line) are well powered to detect signals of the magnitude observed in our three groups of subjects. The red line shows the power of a sample size

of six, as described previously21, to detect differences in CpG methylation in unfractionated PBLs. The mean variance (as standard deviation (s.d.)) for the IgE-associated loci was 0.036 in

PBLs from our primary MRCA panel and 0.023 in the whole blood normal samples from ref. 21, demonstrating that our results were consistent with the previous experiment. SUPPLEMENTARY

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ARTICLE Liang, L., Willis-Owen, S., Laprise, C. _et al._ An epigenome-wide association study of total serum immunoglobulin E concentration. _Nature_ 520, 670–674 (2015).

https://doi.org/10.1038/nature14125 Download citation * Received: 29 January 2014 * Accepted: 27 November 2014 * Published: 18 February 2015 * Issue Date: 30 April 2015 * DOI:

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