Laboratory of Haematology, La Timone Hospital, Marseille, France.
Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé(UMR_S) 1062, Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, Marseille, France.
Sci Rep. 2017 Apr 4;7:45507. doi: 10.1038/srep45507.
Hereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06-10.64] (p = 1.73 10). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10, mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals.
遗传性蛋白 S（PS）缺乏症是一种罕见的凝血障碍，与静脉血栓形成（VT）的风险增加有关。PS Heerlen（PSH）突变是一种罕见的 S501P 突变，最初被认为是一种中性多态性。然而，后来的研究表明，PSH 在体内的半衰期较短，这可能解释了 PSH 杂合子与血浆游离 PS（FPS）水平轻度降低的相关性。PSH 携带者的 VT 风险是否增加仍不清楚。我们分析了四个独立病例对照研究中的 4173 名 VT 患者和 5970 名健康个体中 PSH（rs121918472 A/G）与 VT 的相关性。在 1257 名 VT 患者的亚样本中进行了 FPS 水平的定量测定。在所研究的人群中，AG 基因型与 VT 风险增加 6.57 [4.06-10.64]（p = 1.73 10）相关。在排除 PS 缺乏的 VT 患者中，与无 PSH 的个体相比，PSH 个体的血浆 FPS 水平显著降低[72 + 13 与 91 + 21 UI/dL；p = 1.86 10，PSH 携带者（n = 21）或对照者（n = 1236）的平均值 + SD]。我们提供了强有力的证据表明，罕见的 PSH 变体与未选择个体中的 VT 相关。
