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.