Michelle Daya1, Corey Cox1, Nathalie Acevedo2, Meher P Boorgula1, Monica Campbell1, Sameer Chavan1, Michael H Cho3, Gloria L David4, Priyadarshini Kachroo5, Jessica Lasky-Su5, Xingnan Li6, Caitlin P McHugh7, Dandi Qiao5, Nicholas Rafaels1, Lisa A Beck8, Eugene R Bleecker6, Luis Caraballo2, Adrienne L Cupples9, Camila A Figueiredo10, Richard L Gallo11, Jon Hanifin12, Nadia N Hansel13, Tissa R Hata11, Craig P Hersh5, Jennifer Knight-Madden14, Donald Y M Leung15, Emma Guttman-Yassky16, Deborah A Meyers6, George O'Connor17, Carole Ober18, Peck Y Ong19, Victor E Ortega20, Amy S Paller21, Nirupama Putcha13, Robert M Reed22, Lynda C Schneider23, Edwin K Silverman5, Mark K Slifka12, Jonathan M Spergel24, Ramachandran S Vasan25, Karine A Viaud-Martinez26, Harold Watson27, Scott T Weiss5, Ingo Ruczinski28, Terri H Beaty29, Rasika A Mathias29, Kathleen C Barnes30. 1. Department of Medicine, University of Colorado, Aurora, Colo. 2. Institute for Immunological Research, University of Cartagena, Cartagena, Colombia. 3. Channing Division of Network Medicine and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. 4. Rho, Inc, Durham. 5. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. 6. Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz. 7. Department of Biostatistics, University of Washington, Seattle, Wash. 8. University of Rochester Medical Center, Rochester, NY. 9. Department of Biostatistics, Boston University School of Public Health, Boston, Mass. 10. Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, Brazil. 11. University of California San Diego, San Diego, Calif. 12. Oregon Health & Science University, Portland, Ore. 13. Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Md. 14. Caribbean Institute for Health Research, The University of the West Indies Kingston, Kingston, Jamaica. 15. Division of Pediatric Allergy & Immunology, National Jewish Health, Denver, Colo. 16. Icahn School of Medicine at Mount Sinai, New York, NY. 17. Department of Medicine, Boston University School of Medicine, Boston, Mass. 18. Department of Human Genetics, University of Chicago, Chicago, Ill. 19. Division of Clinical Immunology and Allergy, Children's Hospital Los Angeles and University of Southern California, Los Angeles, Calif. 20. Department of Internal Medcinie, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, NC. 21. Northwestern University and Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill. 22. University of Maryland School of Medicine, Baltimore, Md. 23. Boston Children's Hospital and Harvard Medical School. 24. Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pa. 25. Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Mass; Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Mass. 26. Illumina Laboratory Services, Illumina, Inc, San Diego, Calif. 27. Faculty of Medical Sciences, The University of the West Indies, Queen Elizabeth Hospital, Bridgetown, St. Michael, Barbados. 28. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md. 29. Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md. 30. Department of Medicine, University of Colorado, Aurora, Colo. Electronic address: Kathleen.Barnes@cuanschutz.edu.
Abstract
BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. RESULTS: We identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8). CONCLUSION: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. RESULTS: We identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8). CONCLUSION: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
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