Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients
| Autor: | Francisco Vidal, Marta Martorell, Lorena Ramírez, Irene Corrales, Sofia Alonso, María Teresa Álvarez-Román, Nina Borràs, Ramiro Núñez, Iris Garcia-Martínez, Juan Eduardo Megías-Vericat, Carme Altisent, Rafael Parra |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
congenital hereditary and neonatal diseases and abnormalities Candidate gene Adolescent Receptors Cell Surface Endogeny Hemophilia A Polymorphism Single Nucleotide ABO Blood-Group System law.invention Young Adult Pharmacokinetics law hemic and lymphatic diseases ABO blood group system Humans Medicine Lectins C-Type Allele Child Factor VIII business.industry Hematology Galactosyltransferases Recombinant Proteins Pharmacogenomic Testing Pharmacogenomics Immunology Recombinant DNA Personalized medicine business Cell Adhesion Molecules |
| Zdroj: | Thrombosis and Haemostasis. 120:1395-1406 |
| ISSN: | 2567-689X 0340-6245 |
| Popis: | The pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained. |
| Databáze: | OpenAIRE |
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