LSBR 0820

Genome Wide Association Study (GWAS) to identify genetic risk factors for blood group alloimmunisation. (LSBR 0820)
Project leader: Prof. Dr. C.E. van der Schoot (Dept. of Experimental Immunohematology, Sanquin, Amsterdam), co-applicants: Prof. Dr. W.H. Ouwehand (Dept. of Medicine, Cambridge, United Kingdom) and Prof. Dr. A. Brand (Transfusion Medicine, LUMC, Leiden)
Postdoc investigator: Dr. Barbera Veldhuisen (Jan. 2010 – Nov. 2014)
Senior technician: Onno Verhagen (Mar. 2012 – Dec. 2014)

Blood for transfusion is normally only matched for the ABO and D groups and not for the other red cell blood groups or so-called minor blood groups. The consequence is that approximately 3% of patients develop irregular erythrocyte antibodies (IEA) against one or several of the minor blood groups after a transfusion. In pregnancy approximately 0.3% of women develop IEA. Only 20% of patients who receive regular blood transfusions, e.g. haemoglobinopathy patients, form antibodies. Altogether, this suggests that some individuals are more prone to alloimmunisation against minor blood groups than others. It is postulated that sequence variation in known (e.g. HLA class II) and in a large number of hitherto unknown loci modify the overall risk of IEA formation. To identify these genetic risk factors we have collected nearly 3500 DNA samples from women who became alloimmunised during pregnancy against RhD, in combination with control cohorts from the same populations. A genome-wide association study has been performed on these samples, which is currently being analysed.
For the Dutch samples we have performed an interim analysis on the Fcγ receptor (FcγR) profile, to investigate whether the risk of immunization against RhD during pregnancy can partly be explained by DNA polymorphisms at the FcγR locus, and determining failure of prophylaxis. We observed in alloimmunised women an increased frequency (p=0.0021) of the FCGR2C-ORF, expressing a functional copy of the activating Fcγ receptor FcγRIIc, which is in most individuals a pseudogene. Analysing these data in relation to immunoprophylaxis revealed that increased expression of the FcγRIIc is most likely associated with immunization risk and not with failure of prophylaxis, showing the validity of our approach to analyse RhD-immunized women as a population to identify high responders. The SNPs associated with high respondership will give insight in the biological determinants for alloimmunisation, which can be used to tailor preventive matching in blood transfusion.