Complement blockade by eculizumab is clinically effective in hemolytic Paroxysmal Nocturnal Hemoglobinuria. However, the response is variable and some patients remain red blood cell transfusion-dependent. In 72 patients with hemolytic Paroxysmal Nocturnal Hemoglobinuria on eculizumab we tested the hypothesis that response may depend on genetic polymorphisms of complement-related genes. We found no correlation between the Complement Component C3 genotypes and the need for blood transfusion. On the other hand, we found a significant correlation with the HindIII polymorphism of a complement regulatory gene, the Complement Receptor 1 (CR1) gene. At this locus two co-dominant alleles are known, of which H (common) is associated with high expression, whereas L (rare) is associated with low expression of CR1 on red cells. Patients who still need blood transfusion on eculizumab were 18% among H/H homozygotes, 33% among H/L heterozygotes, and 68% among L/L homozygotes (P=0.016). Thus, patients with Paroxysmal Nocturnal Hemoglobinuria who have the L/L genotype are 7 times more likely to be sub-optimal responders to eculizumab. Both in vitro and in vivo we found that the CR1 HindIII genotype correlates with the abundance of paroxysmal nocturnal hemoglobinuria red cells that have bound C3, and with the kinetics of C3 biding. These results are consistent with the notion that by affecting C3 binding the CR1 genotype influences the response to eculizumab treatment, and this emerges as a novel example of pharmacogenetics.
- paroxysmal nocturnal hemoglobinuria (PNH)