The Asialoglycoprotein Receptor Minor Subunit Gene Contributes to Pharmacokinetics of Factor VIII Concentrates in Hemophilia A.

Background: The asialoglycoprotein receptor (ASGPR) binds with high affinity factor VIII (FVIII) through its -linked oligosaccharides. However, its contribution to the wide inter-individual variation of infused FVIII pharmacokinetics (PK) in hemophilia A (HA) is unknown.

Objective: To investigate the variability in FVIII PK outcomes in relation to genetic variation in the encoding the ASGPR2 subunit.

Methods: Thirty-two HA patients with FVIII:C ≤2 IU/dL underwent 66 single-dose FVIII PK studies. PK parameters were evaluated in relation to 5' untranslated region (5'UTR) polymorphisms, which were investigated by recombinant and white blood cell reverse transcription-polymerase chain reaction approaches.

Results: The 5'UTR polymorphisms determine a frequent and conserved haplotype (HT1) in a regulatory region. The HT1 homozygotes may differ in the amounts of alternatively spliced mRNA transcripts and thus ASGPR2 isoforms. Compared with the other genotypes, the c.-95TT homozygotes ( = 9), showed threefold longer Alpha HL (3.60 hours, 95% confidence interval: 1.44-5.76,  = 0.006), and the c.-95TC heterozygotes ( = 17) showed 25% shorter mean residence time (MRT; 18.5 hours, 15.0-22.0,  = 0.038) and 32% shorter Beta HL (13.5 hours, 10.9-16.0,  = 0.016). These differences were confirmed in patients ( = 27) undergoing PK studies ( = 54) with full-length FVIII only. In different linear regression models, the contribution of the genotypes remained significant after adjustment by genotypes and von Willebrand factor (VWF) antigen levels, and explained 14% (MRT), 15 to 18% (Beta HL), and 22% (Alpha HL) of parameter variability.

Conclusion: Infused FVIII distribution was modulated by frequent genotypes, independently from and together with and VWF antigen levels, which has potential implications for genetically tailored substitutive treatment in HA.