IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
Diabetes. 2013 Oct;62(10):3599-609. doi: 10.2337/db13-0530. Epub 2013 Jun 3.
In patients with diabetes, impaired ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) proteolysis of highly thrombogenic von Willebrand factor (VWF) multimers may accelerate renal and cardiovascular complications. Restoring physiological VWF handling might contribute to ACE inhibitors' (ACEi) reno- and cardioprotective effects. To assess how Pro618Ala ADAMTS13 variants and related proteolytic activity interact with ACEi therapy in predicting renal and cardiovascular complications, we genotyped 1,163 normoalbuminuric type 2 diabetic patients from BErgamo NEphrologic DIabetes Complications Trial (BENEDICT). Interaction between Pro618Ala and ACEi was significant in predicting both renal and combined renal and cardiovascular events. The risk for renal or combined events versus reference Ala carriers on ACEi progressively increased from Pro/Pro homozygotes on ACEi (hazard ratio 2.80 [95% CI 0.849-9.216] and 1.58 [0.737-3.379], respectively) to Pro/Pro homozygotes on non-ACEi (4.77 [1.484-15.357] and 1.99 [0.944-4.187]) to Ala carriers on non-ACEi (8.50 [2.416-29.962] and 4.00 [1.739-9.207]). In a substudy, serum ADAMTS13 activity was significantly lower in Ala carriers than in Pro/Pro homozygotes and in case subjects with renal, cardiovascular, or combined events than in diabetic control subjects without events. ADAMTS13 activity significantly and negatively correlated with all outcomes. In patients with diabetes, ADAMTS13 618Ala variant associated with less proteolytic activity, higher risk of chronic complications, and better response to ACEi therapy. Screening for Pro618Ala polymorphism may help identify patients with diabetes at highest risk who may benefit the most from early reno- and cardioprotective therapy.
在糖尿病患者中，ADAMTS13（一种带有血小板反应蛋白 1 型重复序列的解整合素和金属蛋白酶，成员 13）的活性降低会导致高度血栓形成的血管性血友病因子（VWF）多聚体的分解，从而加速肾脏和心血管并发症的发生。恢复生理 VWF 的处理可能有助于 ACE 抑制剂（ACEi）的肾和心脏保护作用。为了评估 Pro618Ala ADAMTS13 变体和相关的蛋白水解活性如何与 ACEi 治疗相互作用，以预测肾脏和心血管并发症，我们对来自 Bergamo NEphrologic DIabetes Complications Trial（BENEDICT）的 1163 名正常白蛋白尿 2 型糖尿病患者进行了基因分型。Pro618Ala 与 ACEi 之间的相互作用在预测肾脏和肾脏合并心血管事件方面均具有统计学意义。与 ACEi 治疗时 Ala 携带者相比，在 ACEi 治疗时 Pro/Pro 纯合子的肾脏或肾脏合并心血管事件风险逐渐增加（风险比分别为 2.80 [95%CI 0.849-9.216] 和 1.58 [0.737-3.379]），而非 ACEi 治疗时 Pro/Pro 纯合子（4.77 [1.484-15.357] 和 1.99 [0.944-4.187]），而非 ACEi 治疗时 Ala 携带者（8.50 [2.416-29.962] 和 4.00 [1.739-9.207]）。在一项子研究中，Ala 携带者的血清 ADAMTS13 活性明显低于 Pro/Pro 纯合子，并且在患有肾脏、心血管或合并事件的病例患者中明显低于无事件的糖尿病对照患者。ADAMTS13 活性与所有结果均呈显著负相关。在糖尿病患者中，ADAMTS13 618Ala 变体与较低的蛋白水解活性、更高的慢性并发症风险以及对 ACEi 治疗的更好反应相关。筛查 Pro618Ala 多态性可能有助于识别风险最高的糖尿病患者，他们可能从早期的肾和心脏保护治疗中获益最大。
