Blood, 1 February 2008, Vol. 111, No. 3, pp. 1029-1038.
Prepublished online as a Blood First Edition Paper on September 7, 2007; DOI 10.1182/blood-2007-03-079913.
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CLINICAL TRIALS AND OBSERVATIONS
Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura
Willemijn B. Breunis1,2,
Edwin van Mirre2,
Marrie Bruin3,
Judy Geissler2,
Martin de Boer2,
Marjolein Peters1,
Dirk Roos2,
Masja de Haas2,
Harry R. Koene4, and
Taco W. Kuijpers1,2
1 Department of Pediatric Hematology, Immunology and Infectious Disease, Emma Children's Hospital, Academic Medical Center (AMC), Amsterdam;
2 Departments of Blood Cell Research and Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam;
3 Department of Pediatric Hemato-oncology, Wilhelmina Children's Hospital, University Medical Center Utrecht (UMCU), Utrecht; and
4 Department of Hematology, AMC, Amsterdam, The Netherlands
Gene copy number variation (CNV) and single nucleotide polymorphisms (SNPs) count as important sources for interindividual differences, including differential responsiveness to infection or predisposition to autoimmune disease as a result of unbalanced immunity. By developing an 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 (ITP) (present in 34.4% of ITP patients; OR 2.4 (1.3-4.5), P < .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.
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