Blood Group Antigen Combinations and COVID-19: Complexity, Associations and Possible Clinical Relevance

Background: The aim of the study was to investigate whether red blood cell antigens (A, B, D, Cw, C, c, E, e, K, k, Jka, Jkb, Fya, Fyb, Lea, Leb, M, N, S, s, and P1) from clinically relevant blood group systems were associated with susceptibility to COVID-19. Methods: This exploratory case-control study was carried out on a group of 263 donors from the Regional Center for Transfusion Medicine, Bialystok, Poland (including 121 convalescents and 142 healthy subjects). The microplate method was applied to examine the expression of 21 antigens from eight clinically relevant systems in the donors’ red blood cells. Results: No significant correlation was found between any single blood group and susceptibility to COVID-19. For a more detailed analysis, we adopted an approach involving 3-, 4- and 5-element mutual combinations of antigens. In this exploratory analysis of multi-antigen combinations, nominal statistical significance was found for a number of associations, but none remained statistically significant after adjustment for multiple testing. In the case of three-antigen associations, the strongest association was observed for cc combined with Ee and kk, with the effect size showing approximately 4× higher odds of COVID-19 (OR = 4.49, p = 0.020); in the case of four-antigen combinations, the strongest association was found for RhD(+) combined with kk, Fyb and P1(−), as well as RhD(+) combined with cc, Ee and kk, also indicating 4× higher odds of COVID-19 (OR = 4.49 p = 0.016). For five-antigen combinations, the strongest association was observed for blood type O combined with kk, Leb, P1(+) and MM, with the association strength reaching an OR = 4.44, p = 0.025. Conclusions: The findings suggest that analyses based solely on single blood group antigens may have limited value for assessing the susceptibility to COVID-19. In contrast, combinations of red blood cell antigens may provide more reliable correlations with the susceptibility to COVID-19. However, these findings should be interpreted with caution and require confirmation on larger and more representative populations.