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Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Garcia-Martínez I.
  • Borràs N.
  • Martorell M.
  • Parra R.
  • Altisent C.
  • Ramírez L.
  • Álvarez-Román M.T.
  • Nuñez R.
  • Corrales I.
  • Alonso S.
  • Vidal F.

Grupos

Abstract

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. © 2020 Royal Society of Chemistry. All rights reserved.

Datos de la publicación

ISSN/ISSNe:
0340-6245, 2567-689X

THROMBOSIS AND HAEMOSTASIS  GEORG THIEME VERLAG KG

Tipo:
Article
Páginas:
1395-1406
PubMed:
32726853
Enlace a otro recurso:
www.scopus.com
Factor de Impacto:
1,970 SCImago ℠
Cuartil:
Q1 SCImago ℠

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Keywords

  • ABO Blood-Group System; Adolescent; Adult; Cell Adhesion Molecules; Child; Factor VIII; Galactosyltransferases; Hemophilia A; Humans; Lectins, C-Type; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Receptors, Cell Surface; Recombinant Proteins; Young Adult; c type lectin domain family 4 member m; lectin; recombinant blood clotting factor 8; unclassified drug; von Willebrand factor; ABO protein, human; blood clotting factor 8; cell adhesion molecule; cell surface receptor; CLEC4M protein, human; F8 protein, human; galactosyltransferase; lectin; recombinant protein; adolescent; adult; Article; blood group ABO system; body weight; child; clinical article; disease severity; DNA extraction; DNA isolation; gene frequency; genetic analysis; genetic association; genetic variability; genotype; haplotype; hemophilia A; human; intron; male; outcome assessment; personalized medicine; pharmacogenetic testing; priority journal; school child; sequence analysis; single nucleotide polymorphi

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