Nonclassical FCGR2C haplotype is associated with protection from red blood cell alloimmunization in sickle cell disease

Sanne M. Meinderts, Joep W.R. Sins, Karin Fijnvandraat, Sietse Q. Nagelkerke, Judy Geissler, Michael W. Tanck, Christine Bruggeman, Bart J. Biemond, Anita W. Rijneveld, Jean Louis H. Kerkhoffs, Sadaf Pakdaman, Anoosha Habibi, Robin Van Bruggen, Taco W. Kuijpers, France Pirenne, Timo K. Van Den Berg

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Red blood cell (RBC) transfusions are of vital importance in patients with sickle cell disease (SCD). However, a major complication of transfusion therapy is alloimmunization. The low-affinity Fcg receptors, expressed on immune cells, are important regulators of antibody responses. Genetic variation in FCGR genes has been associated with various auto- and alloimmune diseases. The aim of this study was to evaluate the association between genetic variation of FCGR and RBC alloimmunization in SCD. In this case-control study, DNA samples from 2 cohorts of transfused SCD patients were combined (France and The Netherlands). Cases had a positive history of alloimmunization, having received ‡1 RBC unit. Controls had a negative history of alloimmunization, having received ‡20 RBC units. Single nucleotide polymorphisms and copy number variation of the FCGR2/3 gene cluster were studied in a FCGR-specific multiplex ligation-dependent probe amplification assay. Frequencies were compared using logistic regression. Two hundred seventy-two patients were included (130 controls, 142 cases). The nonclassical open reading frame in the FCGR2C gene ( was strongly associated with a decreased alloimmunization risk (odds ratio [OR] 0.26, 95% confidence [CI] 0.11-0.64). This association persisted when only including controls with exposure to ‡100 units (OR 0.30, CI 0.11-0.85) and appeared even stronger when excluding cases with Rh or K antibodies only (OR 0.19, CI 0.06-0.59). In conclusion, SCD patients with the polymorphism have over a 3-fold lower risk for RBC alloimmunization in comparison with patients without this mutation. This protective effect was strongest for exposure to antigens other than the immunogenic Rh or K antigens.

Original languageEnglish
Pages (from-to)2121-2130
Number of pages10
Issue number19
Early online date2017
Publication statusPublished - 9 Nov 2017

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