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 N -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 ASGR2, 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 ASGR2 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 ASGR2 genotypes, the c.-95TT homozygotes ( n  = 9), showed threefold longer Alpha HL (3.60 hours, 95% confidence interval: 1.44-5.76, p  = 0.006), and the c.-95TC heterozygotes ( n  = 17) showed 25% shorter mean residence time (MRT; 18.5 hours, 15.0-22.0, p  = 0.038) and 32% shorter Beta HL (13.5 hours, 10.9-16.0, p  = 0.016). These differences were confirmed in patients ( n  = 27) undergoing PK studies ( n  = 54) with full-length FVIII only. In different linear regression models, the contribution of the ASGR2 genotypes remained significant after adjustment by ABO 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 ASGR2 genotypes, independently from and together with ABO and VWF antigen levels, which has potential implications for genetically tailored substitutive treatment in HA.
Competing Interests: M. Morfini reports personal fees from Kedrion, grants from Pfizer, personal fees from Novo Nordisk, personal fees from Sobi, personal fees from Bayer, personal fees from Bioverativ, personal fees from Octapharma, personal fees from CSL Behring, outside the submitted work. D. Balestra reports grants and personal fees from Bayer. A. Branchini reports grants and personal fees from Pfizer, grants from Bayer, grants and nonfinancial support from Grifols, outside the submitted work. G. Castaman reports personal fees from Roche, personal fees from Bayer, personal fees from Shire, grants and personal fees from CSL Behring, grants and personal fees from Sobi, personal fees from Uniqure, grants from Pfizer, personal fees from Kedrion, personal fees from Novo Nordisk, personal fees from Werfen, outside the submitted work. F. Bernardi reports grants from Bayer, during the conduct of the study; grants from Pfizer, outside the submitted work. The other authors state that they have no conflict of interest.
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