Cheng-Jian Xu1, Olena Gruzieva2, Cancan Qi3, Ana Esplugues4, Ulrike Gehring5, Anna Bergström6, Dan Mason7, Leda Chatzi8, Daniela Porta9, Karin C Lodrup Carlsen10, Nour Baïz11, Anne-Marie Madore12, Harri Alenius6, Bianca van Rijkom13, Soesma A Jankipersadsing13, Pieter van der Vlies14, Inger Kull15, Marianne van Hage16, Mariona Bustamante17, Aitana Lertxundi18, Matias Torrent19, Gillian Santorelli7, Maria Pia Fantini20, Vegard Hovland21, Giancarlo Pesce11, Nanna Fyhrquist22, Tiina Laatikainen23, Martijn C Nawijn24, Yang Li25, Cisca Wijmenga13, Mihai G Netea26, Jean Bousquet27, Josep M Anto28, Catherine Laprise29, Tari Haahtela30, Isabella Annesi-Maesano11, Kai-Håkon Carlsen10, Davide Gori20, Manolis Kogevinas31, John Wright7, Cilla Söderhäll32, Judith M Vonk33, Jordi Sunyer28, Erik Melén34, Gerard H Koppelman3. 1. Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Centre for Individualized Infection Medicine, CiiM, a joint venture between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Xu.Chengjian@mh-hannover.de. 2. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine, Region Stockholm, Stockholm, Sweden. 3. Department of Pediatric Pulmonology and Pediatric Allergy, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 4. Nursing Department, Faculty of Nursing and Chiropody, Universitat de València, València, Spain; FISABIO-Universitat Jaume I-Universitat de València Joint Research Unit of Epidemiology and Environmental Health, València, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. 5. Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands. 6. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 7. Bradford Institute for Health Research, Bradford, United Kingdom. 8. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles. 9. Department of Epidemiology, Lazio Regional Health Service, Rome, Italy. 10. Division of Paediatric and Adolescent Medicine, The Faculty of Medicine, University of Oslo, Oslo, Norway; Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway. 11. Sorbonne University and INSERM, Epidemiology of Allergic and Respiratory Diseases (EPAR) Department, IPLESP, Medical School Saint Antoine, Paris, France. 12. Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Québec City, Canada. 13. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 14. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; HZPC Research BV, Metslawier, The Netherlands. 15. Department of Clinical Sciences and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden. 16. Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden. 17. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Institute of Global Health, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain. 18. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Preventive Medicine and Public Health Department, University of Basque Country (UPV/EHU), Leioa, Bizkaia, Spain; Health Research institute Biodonostia, Donostia-San Sebastian, Gipuzkoa, Spain. 19. Health Research Institute of the Balearic Islands, Spain; ib-salut, Area de Salut de Menorca, Spain. 20. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. 21. Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway. 22. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Human Microbiome Program, Medicum, University of Helsinki, Helsinki, Finland. 23. Finnish Institute for Health and Welfare, Helsinki, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland. 24. GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Pathology and Medical Biology, Experimental Pulmonology and Inflammation Research, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 25. Centre for Individualized Infection Medicine, CiiM, a joint venture between Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. 26. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. 27. University Hospital, Montpellier, France; Department of Dermatology, Charité, Berlin, Germany. 28. CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; ISGlobal, Institute of Global Health, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 29. Département des sciences fondamentales, Université du Québec à Chicoutimi, Saguenay, Québec City, Canada; Centre intersectoriel en santé durable, Université du Québec à Chicoutimi, Saguenay, Québec City, Canada; Centre de santé et de services sociaux du Saguenay-Lac-Saint-Jean, Saguenay, Québec, Canada. 30. Skin and Allergy Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. 31. ISGlobal, Institute of Global Health, Barcelona, Spain. 32. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 33. GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 34. Department of Clinical Sciences and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden; Sachs' Children's Hospital, Stockholm, Sweden.
Abstract
BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.
BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.
Authors: M Innes Asher; Stephen Montefort; Bengt Björkstén; Christopher K W Lai; David P Strachan; Stephan K Weiland; Hywel Williams Journal: Lancet Date: 2006-08-26 Impact factor: 79.321
Authors: Fabián Salazar; Laurence Hall; Ola H Negm; Dennis Awuah; Patrick J Tighe; Farouk Shakib; Amir M Ghaemmaghami Journal: J Allergy Clin Immunol Date: 2015-12-17 Impact factor: 10.793
Authors: Wei Chen; Ting Wang; Maria Pino-Yanes; Erick Forno; Liming Liang; Qi Yan; Donglei Hu; Daniel E Weeks; Andrea Baccarelli; Edna Acosta-Perez; Celeste Eng; Yueh-Ying Han; Nadia Boutaoui; Catherine Laprise; Gwyneth A Davies; Julian M Hopkin; Miriam F Moffatt; William O C M Cookson; Glorisa Canino; Esteban G Burchard; Juan C Celedón Journal: J Allergy Clin Immunol Date: 2017-01-06 Impact factor: 10.793
Authors: B M Quraishi; H Zhang; T M Everson; M Ray; G A Lockett; J W Holloway; S R Tetali; S H Arshad; A Kaushal; F I Rezwan; W Karmaus Journal: Clin Epigenetics Date: 2015-07-21 Impact factor: 6.551
Authors: Cheng-Jian Xu; Marc Jan Bonder; Cilla Söderhäll; Mariona Bustamante; Nour Baïz; Ulrike Gehring; Soesma A Jankipersadsing; Pieter van der Vlies; Cleo C van Diemen; Bianca van Rijkom; Jocelyne Just; Inger Kull; Juha Kere; Josep Maria Antó; Jean Bousquet; Alexandra Zhernakova; Cisca Wijmenga; Isabella Annesi-Maesano; Jordi Sunyer; Erik Melén; Yang Li; Dirkje S Postma; Gerard H Koppelman Journal: BMC Genomics Date: 2017-01-05 Impact factor: 3.969
Authors: Anshul Kundaje; Wouter Meuleman; Jason Ernst; Misha Bilenky; Angela Yen; Alireza Heravi-Moussavi; Pouya Kheradpour; Zhizhuo Zhang; Jianrong Wang; Michael J Ziller; Viren Amin; John W Whitaker; Matthew D Schultz; Lucas D Ward; Abhishek Sarkar; Gerald Quon; Richard S Sandstrom; Matthew L Eaton; Yi-Chieh Wu; Andreas R Pfenning; Xinchen Wang; Melina Claussnitzer; Yaping Liu; Cristian Coarfa; R Alan Harris; Noam Shoresh; Charles B Epstein; Elizabeta Gjoneska; Danny Leung; Wei Xie; R David Hawkins; Ryan Lister; Chibo Hong; Philippe Gascard; Andrew J Mungall; Richard Moore; Eric Chuah; Angela Tam; Theresa K Canfield; R Scott Hansen; Rajinder Kaul; Peter J Sabo; Mukul S Bansal; Annaick Carles; Jesse R Dixon; Kai-How Farh; Soheil Feizi; Rosa Karlic; Ah-Ram Kim; Ashwinikumar Kulkarni; Daofeng Li; Rebecca Lowdon; GiNell Elliott; Tim R Mercer; Shane J Neph; Vitor Onuchic; Paz Polak; Nisha Rajagopal; Pradipta Ray; Richard C Sallari; Kyle T Siebenthall; Nicholas A Sinnott-Armstrong; Michael Stevens; Robert E Thurman; Jie Wu; Bo Zhang; Xin Zhou; Arthur E Beaudet; Laurie A Boyer; Philip L De Jager; Peggy J Farnham; Susan J Fisher; David Haussler; Steven J M Jones; Wei Li; Marco A Marra; Michael T McManus; Shamil Sunyaev; James A Thomson; Thea D Tlsty; Li-Huei Tsai; Wei Wang; Robert A Waterland; Michael Q Zhang; Lisa H Chadwick; Bradley E Bernstein; Joseph F Costello; Joseph R Ecker; Martin Hirst; Alexander Meissner; Aleksandar Milosavljevic; Bing Ren; John A Stamatoyannopoulos; Ting Wang; Manolis Kellis Journal: Nature Date: 2015-02-19 Impact factor: 69.504
Authors: Cheng Peng; Andres Cardenas; Sheryl L Rifas-Shiman; Marie-France Hivert; Diane R Gold; Thomas A Platts-Mills; Xihong Lin; Emily Oken; Andrea A Baccarelli; Augusto A Litonjua; Dawn L DeMeo Journal: Clin Epigenetics Date: 2018-04-17 Impact factor: 6.551
Authors: Pablo Rodriguez Del Rio; Andrew H Liu; Magnus P Borres; Eva Södergren; Fabio Iachetti; Thomas B Casale Journal: Int J Mol Sci Date: 2022-03-31 Impact factor: 5.923
Authors: Marie Standl; Anke Hüls; Anna Kilanowski; Simon Kebede Merid; Sarina Abrishamcar; Dakotah Feil; Elisabeth Thiering; Melanie Waldenberger; Erik Melén; Annette Peters Journal: Clin Epigenetics Date: 2022-09-16 Impact factor: 7.259