TY - JOUR
T1 - Nonclassical FCGR2C haplotype is associated with protection from red blood cell alloimmunization in sickle cell disease
AU - Meinderts, Sanne M.
AU - Sins, Joep W.R.
AU - Fijnvandraat, Karin
AU - Nagelkerke, Sietse Q.
AU - Geissler, Judy
AU - Tanck, Michael W.
AU - Bruggeman, Christine
AU - Biemond, Bart J.
AU - Rijneveld, Anita W.
AU - Kerkhoffs, Jean Louis H.
AU - Pakdaman, Sadaf
AU - Habibi, Anoosha
AU - Van Bruggen, Robin
AU - Kuijpers, Taco W.
AU - Pirenne, France
AU - Van Den Berg, Timo K.
PY - 2017/11/9
Y1 - 2017/11/9
N2 - 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 (FCGR2C.nc-ORF) 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 FCGR2C.nc-ORF 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.
AB - 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 (FCGR2C.nc-ORF) 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 FCGR2C.nc-ORF 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.
UR - http://www.scopus.com/inward/record.url?scp=85033480453&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood-2017-05-784876
DO - https://doi.org/10.1182/blood-2017-05-784876
M3 - Article
C2 - 28899854
SN - 0006-4971
VL - 130
SP - 2121
EP - 2130
JO - Blood
JF - Blood
IS - 19
ER -