title: Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes.
abstract: Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcγ receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P=0.002, OR=1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P=0.023, OR=1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.identifier: http://orcid.org/0000-0002-5159-8802
authors.initials: L
authors.lastname: Franke
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Hanane
authors.initials: H
authors.lastname: el Bannoudi
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Diahann T S L
authors.initials: DT
authors.lastname: Jansen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: Kok
authors.affiliation: Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.affiliation: Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Diogo
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.|Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Morris
authors.initials: M
authors.lastname: Swertz
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.|Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Fransen
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Rachel
authors.initials: R
authors.lastname: Knevel
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Ärlestig
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Greenberg
authors.affiliation: Department of Medicine, Albany Medical College, Albany, New York, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Kremer
authors.affiliation: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Dimitrios A
authors.initials: DA
authors.lastname: Pappas
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.|Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Kanterakis
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Annette H M
authors.initials: AH
authors.lastname: van der Helm-van Mil
authors.affiliation: Laboratory of Genome Structure and Ageing, European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Viktor
authors.initials: V
authors.lastname: Guryev
authors.affiliation: Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden.
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Tom W-J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Andreea
authors.initials: A
authors.lastname: Ioan-Facsinay
authors.affiliation: Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Rene E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.|Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: C445323:FCGR2A protein, human; C499173:FCGR2B protein, human; C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG