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Non-classical FCGR2C haplotype is associated with protection from red blood cell allo-immunization 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 and Timo K. van den Berg

Key points

  • Variation in the Fc gamma receptor gene cluster is associated with protection from RBC allo-immunization in patients with SCD.

  • This association appears to be strongest for allo-immunization to antigens other than the immunogenic Rh or K.

Abstract

Red blood cell (RBC) transfusions are of vital importance in patients with sickle cell disease (SCD). However, a major complication of transfusion therapy is allo-immunization. The low-affinity Fc gamma receptors (FcγRs), expressed on immune cells, are important regulators of antibody responses. Genetic variation in FCGR genes has been associated with various auto- and allo-immune diseases. The aim of this study was to evaluate the association between genetic variation of FCGR and RBC allo-immunization 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 allo-immunization, having received ≥1 RBC unit. Controls had a negative history of allo-immunization, 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 non-classical open reading frame in the FCGR2C gene (FCGR2C.nc-ORF) was strongly associated with a decreased allo-immunization risk (OR 0.26, 95% 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 FCGR2C.nc-ORF polymorphism have over a threefold lower risk for RBC allo-immunization compared to patients without this mutation. This protective effect was strongest for exposure to antigens other than the immunogenic Rh or K antigens.

  • Submitted May 12, 2017.
  • Accepted August 6, 2017.