title: Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria.
abstract: Complement blockade by eculizumab is clinically effective in hemolytic paroxysmal nocturnal hemoglobinuria. However, the response is variable and some patients remain dependent on red blood cell transfusions. 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 transfusions. 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 blood cells. Patients who still needed blood transfusion on eculizumab accounted for 18% of the H/H homozygotes, 33% of the H/L heterozygotes and 68% of the L/L homozygotes (P=0.016). Thus, patients with paroxysmal nocturnal hemoglobinuria who have the L/L genotype are seven 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 binding. 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.
authors.affiliation: lucio.luzzatto@ittumori.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Rondelli
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Risitano
authors.forename: Régis
authors.initials: R
authors.lastname: Peffault de Latour
authors.forename: Michela
authors.initials: M
authors.lastname: Sica
authors.forename: Benedetta
authors.initials: B
authors.lastname: Peruzzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Ricci
authors.forename: Wilma
authors.initials: W
authors.lastname: Barcellini
authors.forename: Anna Paola
authors.initials: AP
authors.lastname: Iori
authors.forename: Carla
authors.initials: C
authors.lastname: Boschetti
authors.forename: Veronica
authors.initials: V
authors.lastname: Valle
authors.forename: Veronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: Maria
authors.initials: M
authors.lastname: De Angioletti
authors.forename: Gerard
authors.initials: G
authors.lastname: Socie
authors.forename: Lucio
authors.initials: L
authors.lastname: Luzzatto
authors.forename: Rosario
authors.initials: R
authors.lastname: Notaro
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D001803:Blood Transfusion; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D003181:Complement C4 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000235:genetics / Q000628:therapy; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D017463:Receptors, Complement 3b / Q000235:genetics / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C509991:CR1 protein, human; D003176:Complement C3; D003181:Complement C4; D017463:Receptors, Complement 3b; C481642:eculizumab
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