OBJECTIVE After aneurysmal subarachnoid haemorrhage (aSAH), extracellular haemoglobin (Hb) in the subarachnoid space is bound by haptoglobin, neutralising Hb toxicity and helping its clearance. Two exons in the HP gene (encoding haptoglobin) exhibit copy number variation (CNV), giving rise to HP1 and HP2 alleles, which influence haptoglobin expression level and possibly haptoglobin function. We hypothesised that the HP CNV associates with long-term outcome beyond the first year after aSAH. METHODS The HP CNV was typed using quantitative PCR in 1299 aSAH survivors in the Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study, a retrospective multicentre cohort study with a median follow-up of 18 months. To investigate mediation of the HP CNV effect by haptoglobin expression level, as opposed to functional differences, we used rs2000999, a single nucleotide polymorphism associated with haptoglobin expression independent of the HP CNV. Outcome was assessed using modified Rankin and Glasgow Outcome Scores. SAH volume was dichotomised on the Fisher grade. Haemoglobin-haptoglobin complexes were measured in cerebrospinal fluid (CSF) of 44 patients with aSAH and related to the HP CNV. RESULTS The HP2 allele associated with a favourable long-term outcome after high-volume but not low-volume aSAH (multivariable logistic regression). However rs2000999 did not predict outcome. The HP2 allele associated with lower CSF haemoglobin-haptoglobin complex levels. The CSF Hb concentration after high-volume and low-volume aSAH was, respectively, higher and lower than the Hb-binding capacity of CSF haptoglobin. CONCLUSION The HP2 allele carries a favourable long-term prognosis after high-volume aSAH. Haptoglobin and the Hb clearance pathway are therapeutic targets after aSAH.

中文翻译：

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动脉瘤性蛛网膜下腔出血后的触珠蛋白基因型和结果。

目的 动脉瘤性蛛网膜下腔出血 (aSAH) 后，蛛网膜下腔的细胞外血红蛋白 (Hb) 与触珠蛋白结合，中和 Hb 毒性并帮助其清除。HP 基因（编码触珠蛋白）中的两个外显子表现出拷贝数变异 (CNV)，从而产生 HP1 和 HP2 等位基因，这会影响触珠蛋白的表达水平，并可能影响触珠蛋白的功能。我们假设 HP CNV 与 aSAH 后第一年之后的长期结果相关。方法 在遗传学和观察性蛛网膜下腔出血 (GOSH) 研究中，使用定量 PCR 对 1299 名 aSAH 幸存者进行 HP CNV 分型，这是一项中位随访时间为 18 个月的回顾性多中心队列研究。为了研究触珠蛋白表达水平对 HP CNV 效应的介导，而不是功能差异，我们使用了 rs2000999，与触珠蛋白表达相关的单核苷酸多态性与 HP CNV 无关。使用改良的 Rankin 和 Glasgow 结果评分评估结果。SAH 体积按 Fisher 等级划分。在 44 名 aSAH 患者的脑脊液 (CSF) 中测量了血红蛋白-触珠蛋白复合物，并与 HP CNV 相关。结果 HP2 等位基因与高容量但不低容量 aSAH（多变量逻辑回归）后的良好长期结果相关。然而 rs2000999 并没有预测结果。HP2 等位基因与较低的 CSF 血红蛋白-触珠蛋白复合物水平相关。高容量和低容量 aSAH 后的 CSF Hb 浓度分别高于和低于 CSF 结合珠蛋白的 Hb 结合能力。结论 HP2 等位基因在高容量 aSAH 后具有良好的长期预后。结合珠蛋白和 Hb 清除途径是 aSAH 后的治疗靶点。