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Eur J Hum Genet. 2016 Feb;24(2):263-70. doi: 10.1038/ejhg.2015.95. Epub 2015 May 13.

Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes.

Author information

1
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
2
Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands.
3
Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
5
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
6
Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
7
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
8
Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden.
9
Department of Medicine, New York University School of Medicine, New York, New York, USA.
10
Department of Medicine, Albany Medical College, Albany, New York, USA.
11
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
12
Laboratory of Genome Structure and Ageing, European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
13
Feinstein Institute for Medical Research, Manhasset, New York, USA.

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.

PMID:
25966632
PMCID:
PMC4717214
DOI:
10.1038/ejhg.2015.95
[Indexed for MEDLINE]
Free PMC Article

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