title: Rare variants at 16p11.2 are associated with common variable immunodeficiency.
abstract: BACKGROUND
  Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients.
  
  
  OBJECTIVE
  We sought to seek novel associations of genes and genetic variants with CVID.
  
  
  METHODS
  We performed association analyses in a discovery cohort of 164 patients with CVID and 19,542 healthy control subjects genotyped on the Immuno BeadChip from Illumina platform; replication of findings was examined in an independent cohort of 135 patients with CVID and 2,066 healthy control subjects, followed by meta-analysis.
  
  
  RESULTS
  We identified 11 single nucleotide polymorphisms (SNPs) at the 16p11.2 locus associated with CVID at a genome-wide significant level in the discovery cohort. The most significant SNP, rs929867 (P = 6.21 × 10(-9)), is in the gene fused-in-sarcoma (FUS), with 4 other SNPs mapping to integrin CD11b (ITGAM). Results were confirmed in our replication cohort. Conditional association analysis suggests a single association signal at the 16p11.2 locus. A strong trend of association was also seen for 38 SNPs (P < 5 × 10(-5)) in the MHC region, supporting that this is a genuine CVID locus. Interestingly, we found that 80% of patients with the rare ITGAM variants have reduced switched memory B-cell counts.
  
  
  CONCLUSIONS
  We report a novel association of CVID with rare variants at the FUS/ITGAM (CD11b) locus on 16p11.2. The association signal is enriched for promoter/enhancer markers in the ITGAM gene. ITGAM encodes the integrin CD11b, a part of complement receptor 3, a novel candidate gene implicated here for the first time in the pathogenesis of CVID.
authors: Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa; Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: S Melkorka
authors: SM
authors: Maggadottir
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Jin
authors: J
authors: Li
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Joseph T
authors: JT
authors: Glessner
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa; Medical Scientist Training Program, Perelman School of Medicine Philadelphia, University of Pennsylvania, Philadelphia, Pa.
authors: Yun Rose
authors: YR
authors: Li
authors: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ.
authors: Zhi
authors: Z
authors: Wei
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Xiao
authors: X
authors: Chang
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Frank D
authors: FD
authors: Mentch
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Kelly A
authors: KA
authors: Thomas
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Cecilia E
authors: CE
authors: Kim
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Yan
authors: Y
authors: Zhao
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Cuiping
authors: C
authors: Hou
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Fengxiang
authors: F
authors: Wang
authors: K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Silje F
authors: SF
authors: Jørgensen
authors: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of South Florida, St Petersburg, Fla.
authors: Elena E
authors: EE
authors: Perez
authors: Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors: Kathleen E
authors: KE
authors: Sullivan
authors: Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Houston, Tex.
authors: Jordan S
authors: JS
authors: Orange
authors: K.G. Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Tom H
authors: TH
authors: Karlsen
authors: Nuffield Department of Medicine, University of Oxford and Oxford Radcliffe Hospital, Oxford, United Kingdom.
authors: Helen
authors: H
authors: Chapel
authors: Institute of Immunology and Department of Medicine, Mount Sinai School of Medicine, New York, NY.
authors: Charlotte
authors: C
authors: Cunningham-Rundles
authors: Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pa; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, Perelman School of Medicine Philadelphia, University of Pennsylvania, Philadelphia, Pa. Electronic address: Hakonarson@email.chop.edu.
authors: Hakon
authors: H
authors: Hakonarson
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002675:Child, Preschool; D002885:Chromosomes, Human, Pair 16; D015331:Cohort Studies; D017074:Common Variable Immunodeficiency / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004742:Enhancer Elements, Genetic; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D007156:Immunologic Memory; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000276:immunology
chemical_list: D039481:CD11b Antigen; C000599550:FUS protein, human; C509295:ITGAM protein, human; D034702:RNA-Binding Protein FUS
keywords: ITGAM; Immunodeficiency; genome-wide association study; immunogenetics; rare variants