Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria

Tommaso Rondelli, Antonio M. Risitano, Régis Peffault de Latour, Michela Sica, Benedetta Peruzzi, Patrizia Ricci, Wilma Barcellini, Anna Paola Iori, Carla Boschetti, Veronica Valle, Veronique Frémeaux-Bacchi, Maria De Angioletti, Gerard Socie, Lucio Luzzatto, Rosario Notaro

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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.

Original languageEnglish
Pages (from-to)262-266
Number of pages5
JournalHaematologica
Volume99
Issue number2
DOIs
Publication statusPublished - Feb 1 2014

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Complement C1
Paroxysmal Hemoglobinuria
Complement Receptors
Genotype
Genes
Homozygote
Blood Transfusion
Erythrocyte Transfusion
Complement C3
Pharmacogenetics
Genetic Polymorphisms
Regulator Genes
Heterozygote
Erythrocytes
Alleles
eculizumab

ASJC Scopus subject areas

  • Hematology

Cite this

Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria. / Rondelli, Tommaso; Risitano, Antonio M.; de Latour, Régis Peffault; Sica, Michela; Peruzzi, Benedetta; Ricci, Patrizia; Barcellini, Wilma; Iori, Anna Paola; Boschetti, Carla; Valle, Veronica; Frémeaux-Bacchi, Veronique; De Angioletti, Maria; Socie, Gerard; Luzzatto, Lucio; Notaro, Rosario.

In: Haematologica, Vol. 99, No. 2, 01.02.2014, p. 262-266.

Research output: Contribution to journalArticle

Rondelli, T, Risitano, AM, de Latour, RP, Sica, M, Peruzzi, B, Ricci, P, Barcellini, W, Iori, AP, Boschetti, C, Valle, V, Frémeaux-Bacchi, V, De Angioletti, M, Socie, G, Luzzatto, L & Notaro, R 2014, 'Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria', Haematologica, vol. 99, no. 2, pp. 262-266. https://doi.org/10.3324/haematol.2013.090001
Rondelli, Tommaso ; Risitano, Antonio M. ; de Latour, Régis Peffault ; Sica, Michela ; Peruzzi, Benedetta ; Ricci, Patrizia ; Barcellini, Wilma ; Iori, Anna Paola ; Boschetti, Carla ; Valle, Veronica ; Frémeaux-Bacchi, Veronique ; De Angioletti, Maria ; Socie, Gerard ; Luzzatto, Lucio ; Notaro, Rosario. / Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria. In: Haematologica. 2014 ; Vol. 99, No. 2. pp. 262-266.
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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.",
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AU - Rondelli, Tommaso

AU - Risitano, Antonio M.

AU - de Latour, Régis Peffault

AU - Sica, Michela

AU - Peruzzi, Benedetta

AU - Ricci, Patrizia

AU - Barcellini, Wilma

AU - Iori, Anna Paola

AU - Boschetti, Carla

AU - Valle, Veronica

AU - Frémeaux-Bacchi, Veronique

AU - De Angioletti, Maria

AU - Socie, Gerard

AU - Luzzatto, Lucio

AU - Notaro, Rosario

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N2 - 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.

AB - 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.

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