DNA methylation in childhood asthma: an epigenome-wide meta-analysis

被引：172

作者：

Xu, Cheng-Jian ^{[1
,2
,3
]}

Soderhall, Cilla ^{[6
,7
]}

Bustamante, Mariona ^{[9
,10
,11
,12
]}

Baiz, Nour ^{[13
]}

Gruzieva, Olena ^{[8
]}

Gehring, Ulrike ^{[14
]}

Mason, Dan ^{[16
]}

Chatzi, Leda ^{[17
,18
,19
]}

Basterrechea, Mikel ^{[12
,20
,21
]}

Llop, Sabrina ^{[12
,22
]}

Torrent, Maties ^{[23
]}

Forastiere, Francesco ^{[24
]}

Fantini, Maria Pia ^{[25
]}

Carlsen, Karin C. Lodrup ^{[26
,27
]}

Haahtela, Tari ^{[28
]}

Morin, Andreanne ^{[30
,31
]}

Kerkhof, Marjan ^{[2
]}

Merid, Simon Kebede ^{[8
]}

van Rijkom, Bianca ^{[3
]}

Jankipersadsing, Soesma A. ^{[1
,3
]}

Bonder, Marc Jan ^{[3
]}

Ballereau, Stephane ^{[32
,33
]}

Vermeulen, Cornelis J. ^{[1
,2
]}

Aguirre-Gamboa, Raul ^{[3
]}

de Jongste, Johan C. ^{[34
]}

Smit, Henriette A. ^{[15
]}

Kumar, Ashish ^{[8
,35
,36
]}

Pershagen, Goran ^{[8
]}

Guerra, Stefano ^{[9
,37
]}

Garcia-Aymerich, Judith ^{[9
,11
,12
]}

Greco, Dario ^{[38
,39
]}

Reinius, Lovisa ^{[7
]}

McEachan, Rosemary R. C. ^{[16
]}

Azad, Raf ^{[16
]}

Hovland, Vegard ^{[26
]}

Mowinckel, Petter ^{[26
]}

Alenius, Harri ^{[8
,29
]}

Fyhrquist, Nanna ^{[8
,29
]}

Lemonnier, Nathanael ^{[32
,40
]}

Pellet, Johann ^{[32
]}

Auffray, Charles ^{[32
]}

van der Vlies, Pieter ^{[3
,41
]}

van Diemen, Cleo C. ^{[3
]}

Li, Yang ^{[3
]}

Wijmenga, Cisca ^{[3
]}

Netea, Mihai G. ^{[43
,44
]}

Moffatt, Miriam F. ^{[42
]}

Cookson, William O. C. M. ^{[42
]}

Anto, Josep M. ^{[9
,11
,12
,53
]}

Bousquet, Jean ^{[45
,46
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst Groningen, Groningen, Netherlands

[3] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[4] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol Expt Pulmonol & Inflammat, Groningen, Netherlands

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergy, Beatrix Childrens Hosp, Groningen, Netherlands

[6] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

[7] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden

[8] Karolinska Inst, Inst Environm Med, Stockholm, Sweden

[9] Barcelona Inst Sci & Technol, ISGlobal, Ctr Res Environm Epidemiol, Barcelona, Spain

[10] Barcelona Inst Sci & Technol, Ctr Genom Regulat, Barcelona, Spain

[11] Univ Pompeu Fabra, Barcelona, Spain

[12] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain

[13] Sorbonne Univ, Saint Antoine Med Sch, Pierre Louis Inst Epidemiol & Publ Hlth, INSERM,Epidemiol Allerg & Resp Dis Dept EPAR, Paris, France

[14] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands

[15] Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, Univ Med Ctr Utrecht, Utrecht, Netherlands

[16] Bradford Teaching Hosp NHS Fdn Trust, Bradford Inst Hlth Res, Bradford, W Yorkshire, England

[17] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA

[18] Univ Crete, Dept Social Med, Fac Med, Iraklion, Crete, Greece

[19] Maastricht Univ, Fac Hlth Med & Life Sci, Dept Genet & Cell Biol, Maastricht, Netherlands

[20] Hlth Res Inst Biodonostia, San Sebastian, Spain

[21] Publ Hlth Dept Gipuzkoa, San Sebastian, Spain

[22] Univ Valencia, Univ Jaume 1, FISABIO, Epidemiol & Environm Hlth Joint Res Unit, Valencia, Spain

[23] Ib Salut, Area Salut Menorca, Menorca, Spain

[24] Lazio Reg Hlth Serv, Dept Epidemiol, Rome, Italy

[25] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy

[26] Oslo Univ Hosp, Dept Paediat, Oslo, Norway

[27] Univ Oslo, Dept Paediat & Adolescent Med, Oslo, Norway

[28] Univ Helsinki, Skin & Allergy Hosp, Helsinki Univ Hosp, Helsinki, Finland

[29] Univ Helsinki, Dept Bacteriol & Immunol Medicum, Helsinki, Finland

[30] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[31] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[32] Univ Lyon, CIRI CNRS UMR5308, CNRS ENS UCBL ENS, European Inst Syst Biol & Med, Campus Charles Merieux, Lyon, France

[33] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England

[34] Univ Med Ctr, Dept Pediat, Sophia Childrens Hosp, Erasmus MC,Dept Pediat, Rotterdam, Netherlands

[35] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland

[36] Univ Basel, Basel, Switzerland

[37] Univ Arizona, Asthma & Airway Dis Res Ctr, Tucson, AZ USA

[38] Univ Tampere, Fac Med & Life Sci, Tampere, Finland

[39] Univ Tampere, Inst Biosci & Med Technol BioMediTech, Tampere, Finland

[40] UGA, Inst Adv Biosci, INSERM U1209, CNRS UMR5309, Site Sante,Allee Alpes, La Tronche, France

[41] Res BV, Metslawier, Netherlands

[42] Imperial Coll London, Natl Heart & Lung Inst, London, England

[43] Radboud Univ Nijmegen, Dept Internal Med, Med Ctr, Nijmegen, Netherlands

[44] Radboud Univ Nijmegen, Radboud Ctr Infect Dis, Med Ctr, Nijmegen, Netherlands

[45] Univ Hosp, Montpellier, France

[46] Charite, Dept Dermatol, Berlin, Germany

[47] Natl Inst Hlth & Welf, Helsinki, Finland

[48] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland

[49] Univ Quebec Chicoutimi, Dept Sci Fondamentales, Saguenay, PQ, Canada

[50] Ctr Integre Univ, Sante & Serv Sociaux Saguenay Lac St Jean, 305 St Vallier, Saguenay, PQ, Canada

来源：

LANCET RESPIRATORY MEDICINE | 2018年 / 6卷 / 05期

关键词：

GENOMEWIDE ASSOCIATION; PHENOTYPES; CHILDREN; COHORT; IGE; POPULATION; COLLECTION; EXPOSURE; RHINITIS; IMMUNITY;

D O I：

10.1016/S2213-2600(18)30052-3

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Background DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1 . 14 x 10(-7)) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects. Interpretation Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.

引用

页码：379 / 388

页数：10

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