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. 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.

中文翻译：

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去唾液酸糖蛋白受体小亚基基因有助于血友病 A 中因子 VIII 浓缩物的药代动力学

背景 去唾液酸糖蛋白受体 (ASGPR) 通过其 N-连接寡糖与高亲和力因子 VIII (FVIII) 结合。然而，它对血友病 A (HA) 中输注的 FVIII 药代动力学 (PK) 的广泛个体间差异的贡献尚不清楚。目的研究 FVIII PK 结果与编码 ASGPR2 亚基的 ASGR2 遗传变异相关的变异性。方法 32 名 FVIII:C ≤2 IU/dL 的 HA 患者接受了 66 项单剂量 FVIII PK 研究。PK 参数与 ASGR2 5' 非翻译区 (5'UTR) 多态性相关，通过重组和白细胞逆转录聚合酶链反应方法进行研究。结果 5'UTR 多态性决定了调控区域中频繁且保守的单倍型（HT1）。HT1 纯合子的可变剪接 mRNA 转录物的数量可能不同，因此 ASGPR2 同种型也可能不同。与其他 ASGR2 基因型相比，c.-95TT 纯合子（n = 9）的 Alpha HL（3.60 小时，95% 置信区间：1.44-5.76，p = 0.006）和 c.-95TC 杂合子（ n = 17）显示平均停留时间缩短了 25%（MRT；18.5 小时，15.0-22.0，p = 0.038）和 32% 的 Beta HL（13.5 小时，10.9-16.0，p = 0.016）。这些差异在仅接受全长 FVIII 的 PK 研究 (n = 54) 的患者 (n = 27) 中得到证实。在不同的线性回归模型中，通过 ABO 基因型和血管性血友病因子（VWF）抗原水平调整后，ASGR2 基因型的贡献仍然显着，并解释了 14%（MRT）、15% 至 18%（Beta HL）和 22%（参数可变性的 Alpha HL)。