Genome-wide association identifies diverse causes of common variable immunodeficiency

• Type of Material: Article
• Authors: Jordan S. Orange, University of Pennsylvania; Joseph T. Glessner, Children’s Hospital of Philadelphia; Elena Resnick, Mount Sinai School of Medicine; Kathleen E. Sullivan, University of Pennsylvania; Mary Lucas, University of Oxford; Berne Ferry, University of Oxford; Cecilia E. Kim, Children’s Hospital of Philadelphia; Cuiping Hou, Children’s Hospital of Philadelphia; Fengziang Wang, Children’s Hospital of Philadelphia; Rosetta Chiavacci, Children’s Hospital of Philadelphia; Subramaniam Kugathasan, Emory University; John W. Sleasman, University of South Florida; Robert Baldassano, University of Pennsylvania; Elena E. Perez, University of South Florida; Helen Chapel, University of Oxford; Charlotte Cunningham-Rundles, Mount Sinai School of Medicine; Hakon Hakonarson, Children's Hospital of Philadelphia
• Language: English
• Date: 2011-06-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 American Academy of Allergy, Asthma & Immunology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaci.2011.02.039
• Title of Journal or Parent Work: Journal of Allergy and Clinical Immunology
• ISSN: 0091-6749
• Volume: 127
• Issue: 6
• Start Page: 1360
• End Page: U79
• Grant/Funding Information: Children’s Hospital of Philadelphia support was from the Children’s Hospital of Philadelphia Institutional Development Award to the Center for Applied Genomics, which funded all genotyping (to H.H.); a Research Development Award from the Cotswold Foundation (to H.H.); the Jeffrey Modell foundation (to J.S.O.); and National Institutes of Health (NIH) grant AI-079731 (to J.S.O.).; Oxford support was from the NIHR Oxford Biomedical Research Centre, Baxter Healthcare (general support to the department not specific to this project), Talecris (general support to the department not specific to this project), and the Jeffrey Modell Foundation for unrestricted gifts; the Primary Immunodeficiency Association for the Centre of Excellence award; and the European Commission for EU 7th FP EURO-PADnet number 201549.; University of South Florida support was from NIH grant 5R03AI083904 (to E.E.P.).; Mount Sinai support was from NIH grants, AI-101093, AI-467320, AI-48693, NIAID Contract 03-22, and the David S Gottesman Immunology Chair (all to C.C.-R.).
• Keywords: DISORDERS; immunodiagnostics; genome-wide association; DISEASE; SUSCEPTIBILITY; Allergy; GENE; Science & Technology; Life Sciences & Biomedicine; Primary immunodeficiency; IGA DEFICIENCY; MACROPHAGES; antibody deficiency; copy number variation; common variable immunodeficiency; VARIANTS; UPDATE; genetics; Immunology; MUTATIONS; MANAGEMENT
• Research Categories: Biology, Genetics; Health Sciences, Immunology

Abstract

Background: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities. Objective: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID. Methods: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs). Patients were divided into a discovery cohort of 179 cases in comparison with 1,917 control subjects and a replication cohort of 109 cases and 1,114 control subjects. Results: Our analyses detected strong association with the MHC region and association with a disintegrin and metalloproteinase (ADAM) genes (P combined = 1.96 × 10-7) replicated in the independent cohort. CNV analysis defined 16 disease-associated deletions and duplications, including duplication of origin recognition complex 4L (ORC4L) that was unique to 15 cases (P = 8.66 × 10-16), as well as numerous unique rare intraexonic deletions and duplications suggesting multiple novel genetic causes of CVID. Furthermore, the 1,000 most significant SNPs were strongly predictive of the CVID phenotype by using a Support Vector Machine algorithm with positive and negative predictive values of 1.0 and 0.957, respectively. Conclusion: Our integrative genome-wide analysis of SNP genotypes and CNVs has uncovered multiple novel susceptibility loci for CVID, both common and rare, which is consistent with the highly heterogeneous nature of CVID. These results provide new mechanistic insights into immunopathogenesis based on these unique genetic variations and might allow for improved diagnosis of CVID based on accurate prediction of the CVID clinical phenotypes by using our Support Vector Machine model.