The asialoglycoprotein receptor minor subunit gene (ASGR2) 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. Patients/Methods Thirty‐two HA patients with FVIII:C ≤ 2 IU/dL underwent 66 single dose FVIII PKs. PK parameters were evaluated in relation to ASGR2 5’ untranslated region (5’UTR) polymorphisms, that were investigated by recombinant and white blood cell RT-PCR 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 to the other ASGR2 genotypes, the c.-95TT homozygotes (n=9), showed three-fold longer Alpha HL (3.60 h, 95% CI 1.44-5.76, p=0.006), and the c.-95TC heterozygotes (n=17) showed 25% shorter MRT (18.5 h, 15.0-22.0, p=0.038) and 32% shorter Beta HL (13.5 h, 10.9-16.0, p=0.016). These differences were confirmed in patients (n=27) undergoing PKs (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 VWF:Ag levels, and explained 14% (MRT), 15-18% (Beta HL) and 22% (Alpha HL) of parameter variability. Conclusions 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.