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A substantial hurdle for successful xenotransplantation is to negate the effect of xenoreactive natural antibodies [mainly Galα1–3Galβ1–4GlcNAc (α-Gal) specific] that cause hyperacute xenograft rejection. Galα1–3Gal molecules (α-Gal) have close structural homology with human ABO blood groups and therefore an individual's blood group might influence the formation of α-Gal specific antibodies. Genetic heterogeneity controlling α-Gal specific antibody formation could have important implications for future pig to human xenotransplantation clinical trials. We have investigated the relationship between ABO blood group and immunoglobulin M (IgM) and immunoglobulin G (IgG) α-Gal specific antibody titres in sera obtained from renal dialysis patients and healthy blood donors.Serially diluted sera (n = 166) obtained from renal dialysis patients awaiting kidney transplantation (n = 116) and healthy blood donors (n = 50) were tested for IgM and IgG α-Gal antibodies using an enzyme-linked immunosorbent assay (ELISA) specific for α-Gal. The study cohort comprised 62, 48, 36 and 20 sera obtained from blood group O, A, B and AB individuals, respectively. Reciprocal α-Gal specific antibody titres were calculated from ELISA titration curves and stratified by individual blood group.No significant heterogeneity was found in IgM α-Gal specific antibody titres across ABO blood groups. In contrast, marked heterogeneity was observed in IgG α-Gal specific antibody titres when stratified by blood group. IgG α-Gal specific antibody titres were higher in sera obtained from blood group O renal dialysis patients [median titre 40, interquartile range (IQR) 14 to 72], compared with blood group A (median titre 18, IQR 7 to 54, P = 0.05), blood group B (median titre 6, IQR 0 to 15, P < 0.001) and blood group AB patients (median titre 3.5, IQR 0 to 16, P = 0.002). A similar correlation was found for IgG α-Gal specific antibody titres in sera obtained from healthy blood donors with median titres of 20 (IQR 12 to 34), 37 (10 to 91), 9 (0 to 20), and 5.5 (0 to 12) in blood groups O, A, B and AB individuals, respectively. There was a strong interrelationship between α-Gal specific antibody class and blood group, with both IgM and IgG α-Gal specific antibodies found in 84% of the blood group O sera, 73% of blood group A sera, 50% of blood group B sera and 40% of blood group AB sera (P < 0.001). In a subgroup of 39 renal dialysis patients, IgM and IgG α-Gal specific antibody titres were measured in two serum samples obtained at different time-points (median time interval 581 days, range 42 to 4414), and showed a high degree of stability (correlation coefficient 0.88 and 0.90 for IgM and IgG, respectively).IgG α-Gal specific antibody titres are significantly higher in the sera of blood group O and A renal dialysis patients and healthy individuals compared with blood groups B and AB. These data indicate that future clinical trials of pig to human xenotransplantation may be more problematic for non-blood group B patients who are likely to have high levels of IgG α-Gal specific antibodies that are associated with acute vascular rejection.