Submitted March 13, 2007
Accepted August 23, 2007
Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura
Willemijn B. Breunis, Edwin van Mirre, Marrie Bruin, Judy Geissler, Martin de Boer, Marjolein Peters, Dirk Roos, Masja de Haas, Harry R. Koene, and Taco W. Kuijpers*
Dept. of Pediatric Hematology, Immunology & Infectious Dis., Emma Children's Hospital, Academic Medical Center, Amsterdam, Netherlands
Dept. of Blood Cell Research, and Dept. of Immunohematology, Sanquin Research at CLB and Landsteiner Laboratory, Amsterdam, Netherlands
Dept of Pediatric Hemato-oncology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
Dept. of Hematology, Academic Medical Center, Amsterdam, Netherlands
* Corresponding author; email: t.w.kuijpers{at}amc.uva.nl.
Gene copy number variation (CNV) and single nucleotide polymorphisms (SNPs) count as important sources for inter-individual differences, including differential responsiveness to infection or predisposition to autoimmune disease as a result of unbalanced immunity.
By developing a FCGR-specific multiplex ligation-dependent probe amplification assay we were able to study a notoriously complex and highly homologous region in the human genome and demonstrate extensive variation in the FCGR2 and FCGR3 gene clusters, including previously unrecognized CNV.
As indicated by the prevalence of an open reading frame of FCGR2C, Fc
receptor (FcR) type IIc is expressed in 18% of healthy individuals and is strongly associated with the hematological autoimmune disease idiopathic thrombocytopenic purpura (present in 34.4% of ITP patients; OR 2.4 (1.3-4.5), p<0.009). FcRIIc acts as an activating IgG receptor that exerts antibody-mediated cellular cytotoxicity by immune cells. Therefore, we propose that the activating FCGR2C-ORF genotype predisposes to ITP by altering the balance of activating and inhibitory FcR on immune cells.
