Yuka Asai1, Aida Eslami2, C Dorien van Ginkel3, Loubna Akhabir2, Ming Wan2, George Ellis2, Moshe Ben-Shoshan4, David Martino5, Manuel A Ferreira6, Katrina Allen5, Bruce Mazer4, Hans de Groot7, Nicolette W de Jong8, Roy N Gerth van Wijk8, Anthony E J Dubois3, Rick Chin9, Stephen Cheuk10, Joshua Hoffman11, Eric Jorgensen12, John S Witte11, Ronald B Melles13, Xiumei Hong14, Xiaobin Wang14, Jennie Hui15, Arthur W Bill Musk16, Michael Hunter17, Alan L James18, Gerard H Koppelman3, Andrew J Sandford2, Ann E Clarke12, Denise Daley19. 1. Division of Dermatology, Department of Medicine, Queen's University, Kingston, and the Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec, Canada. 2. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada. 3. University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology and University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands. 4. Division of Allergy and Immunology, Department of Pediatrics, Montreal Children's Hospital, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. 5. Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Australia. 6. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 7. Department of Pediatric Allergology, Diaconessenhuis Voorburg, Reinier de Graaf Gasthuis, Delft, The Netherlands. 8. Erasmus MC, Department of Allergology, Rotterdam, The Netherlands. 9. Division of Rheumatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. 10. Private Practice, Calgary, Alberta. 11. Department of Epidemiology and Biostatistics, University of California, San Francisco, Calif. 12. Division of Research, Kaiser Permanente Northern California, Oakland, Calif. 13. Department of Ophthalmology, Kaiser Permanente Northern California, Redwood City Medical Center, Redwood City, Calif. 14. Department of Population, Family and Reproductive Health, Center on the Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md. 15. School of Population Health, University of Western Australia, Australia and Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia. 16. Department of Respiratory Medicine, Sir Charles Gairdner Hospital, and School of Population Health, University of Western Australia, Perth, Australia. 17. School of Population Health, University of Western Australia, Perth, Australia. 18. Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. 19. Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: denise.daley@hli.ubc.ca.
Abstract
BACKGROUND: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. OBJECTIVE: We sought to investigate genetic susceptibility to PA. METHODS: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. RESULTS: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10-8), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10-6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10-11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10-6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30. CONCLUSION: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.
BACKGROUND:Peanutallergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. OBJECTIVE: We sought to investigate genetic susceptibility to PA. METHODS: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. RESULTS: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10-8), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10-6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10-11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10-6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30. CONCLUSION: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.
Authors: Huaqin Pan; Stephen W Edwards; Cataia Ives; Hannah Covert; Emily W Harville; Maureen Y Lichtveld; Jeffrey K Wickliffe; Carol M Hamilton Journal: Curr Opin Toxicol Date: 2019-07-30
Authors: Alexandra Winters; Henry T Bahnson; Ingo Ruczinski; Meher P Boorgula; Claire Malley; Ali R Keramati; Sameer Chavan; David Larson; Karen Cerosaletti; Peter H Sayre; Marshall Plaut; George Du Toit; Gideon Lack; Kathleen C Barnes; Gerald T Nepom; Rasika A Mathias Journal: J Allergy Clin Immunol Date: 2019-02-27 Impact factor: 10.793
Authors: Anh N Do; Corey T Watson; Ariella T Cohain; Robert S Griffin; Alexander Grishin; Robert A Wood; A Wesley Burks; Stacie M Jones; Amy Scurlock; Donald Y M Leung; Hugh A Sampson; Scott H Sicherer; Andrew J Sharp; Eric E Schadt; Supinda Bunyavanich Journal: J Allergy Clin Immunol Date: 2019-12-12 Impact factor: 10.793
Authors: Kelly Orgel; Johanna M Smeekens; Ping Ye; Lauren Fotsch; Rishu Guo; Darla R Miller; Fernando Pardo-Manuel de Villena; A Wesley Burks; Martin T Ferris; Michael D Kulis Journal: J Allergy Clin Immunol Date: 2018-10-19 Impact factor: 10.793