Chloé Sarnowski1, Catherine Laprise2, Giovanni Malerba3, Miriam F Moffatt4, Marie-Hélène Dizier1, Andréanne Morin5, Quentin B Vincent6, Klaus Rohde7, Jorge Esparza-Gordillo8, Patricia Margaritte-Jeannin1, Liming Liang9, Young-Ae Lee7, Jean Bousquet10, Valérie Siroux11, Pier Franco Pignatti3, William O Cookson4, Mark Lathrop12, Tomi Pastinen12, Florence Demenais1, Emmanuelle Bouzigon13. 1. INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France. 2. Université du Québec, à Chicoutimi, Québec, Canada. 3. Section of Biology and Genetics, Department of Mother and Child, and Biology-Genetics, University of Verona, Verona, Italy. 4. National Heart and Lung Institute, Imperial College London, London, United Kingdom. 5. Université du Québec, à Chicoutimi, Québec, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada. 6. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, UMR1163, Paris, France; Université Paris Descartes, Imagine Institute, Paris, France. 7. Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany. 8. Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Centre, Charité Universitätsmedizin Berlin, Berlin, Germany. 9. Department of Epidemiology, Harvard School of Public Health, Boston, Mass. 10. Hôpital Arnaud de Villeneuve, Service des Maladies Respiratoires, Montpellier, France. 11. Université Grenoble Alpes, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France; INSERM, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France; CHU de Grenoble, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France. 12. McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada. 13. INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France. Electronic address: emmanuelle.bouzigon@inserm.fr.
Abstract
BACKGROUND: Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved. OBJECTIVE: We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect. METHODS: We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families. RESULTS: We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association. CONCLUSION: By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.
BACKGROUND:Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved. OBJECTIVE: We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect. METHODS: We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families. RESULTS: We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association. CONCLUSION: By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.
Authors: Sarah K Wise; Sandra Y Lin; Elina Toskala; Richard R Orlandi; Cezmi A Akdis; Jeremiah A Alt; Antoine Azar; Fuad M Baroody; Claus Bachert; G Walter Canonica; Thomas Chacko; Cemal Cingi; Giorgio Ciprandi; Jacquelynne Corey; Linda S Cox; Peter Socrates Creticos; Adnan Custovic; Cecelia Damask; Adam DeConde; John M DelGaudio; Charles S Ebert; Jean Anderson Eloy; Carrie E Flanagan; Wytske J Fokkens; Christine Franzese; Jan Gosepath; Ashleigh Halderman; Robert G Hamilton; Hans Jürgen Hoffman; Jens M Hohlfeld; Steven M Houser; Peter H Hwang; Cristoforo Incorvaia; Deborah Jarvis; Ayesha N Khalid; Maritta Kilpeläinen; Todd T Kingdom; Helene Krouse; Desiree Larenas-Linnemann; Adrienne M Laury; Stella E Lee; Joshua M Levy; Amber U Luong; Bradley F Marple; Edward D McCoul; K Christopher McMains; Erik Melén; James W Mims; Gianna Moscato; Joaquim Mullol; Harold S Nelson; Monica Patadia; Ruby Pawankar; Oliver Pfaar; Michael P Platt; William Reisacher; Carmen Rondón; Luke Rudmik; Matthew Ryan; Joaquin Sastre; Rodney J Schlosser; Russell A Settipane; Hemant P Sharma; Aziz Sheikh; Timothy L Smith; Pongsakorn Tantilipikorn; Jody R Tversky; Maria C Veling; De Yun Wang; Marit Westman; Magnus Wickman; Mark Zacharek Journal: Int Forum Allergy Rhinol Date: 2018-02 Impact factor: 3.858