Identification of genetic polymorphisms that predict responder/non-responder profiles to the RhD antigen

Background: Regular plasma donors who produce high titre anti-D immunoglobulin (Ig) are overseen by the Australian Red Cross Blood Service RhD Program. New donors to the program are immunised with small amounts of RhD-positive RBCs, whilst donors who have developed anti-D due to previous RhD-incompatible blood transfusion or pregnancy are boosted with RhD-positive RBCs to maintain a high level of serum anti-D Ig. A significant proportion of primarily immunised individuals do not respond to RhD immunisation and are therefore unnecessarily exposed to the risks involved in RBC sensitisation. Study design and methods: We genotyped 184 anti-D donors for similar to 9000 immunological and inflammatory genetic polymorphisms on an Affymetrix GeneChip, and validated the results with a High-Resolution Melt analysis assay. We built and validated a predictive logistic regression model using High Responder and Non-Responder anti-D donors that incorporated highly-associated polymorphisms and gender. Results: High Responder and Non-Responder profiles in anti-D donors were significantly associated with a shortlist of 13 genetic polymorphisms and sex of the donor. The derivation of a logistic regression model showed an accuracy rate of 92.6% that was subsequently validated as 60.0% with an independent set of donor samples. Conclusion: This study has developed a logistic regression model and a genotyping assay that can predict the responder profiles of anti-D donors and could potentially be applied to new donors and transfusion-dependent patients in a clinical setting. Additionally, target polymorphisms identified in immunological genes could help to elucidate the immunomodulatory pathways regulating the immune response to the RhD antigen, and to other RBC antigens. (C) 2015 Elsevier Ltd. All rights reserved.