Familial hypercholesterolemia: PCSK9 InsLEU genetic variant and prediabetes/diabetes risk
Familial hypercholesterolemia: PCSK9 InsLEU genetic variant and prediabetes/diabetes risk
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DOI：
10.1016/j.jacl.2015.08.005
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发表时间：
2015-12-01
影响因子：
4.4
通讯作者：
Baass, Alexis
中科院分区：
文献类型：
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作者：
Saavedra, Yascara G. Luna;Dufour, Robert;Baass, Alexis
背景：最近的荟萃分析显示，他汀类药物治疗对新发糖尿病发病率增加具有剂量依赖性影响。前蛋白转化酶枯草杆菌蛋白酶/kexin 型 (PCSK9) 抑制剂是一组重要的新兴降脂疗法。 PCSK9功能丧失突变与低密度脂蛋白胆固醇和心血管风险相关，但其对葡萄糖稳态和糖尿病风险的影响尚不清楚。 目的：我们研究PCSK9-InsLEU多态性对糖尿病前期和糖尿病发生率的影响。方法：对724名家族性高胆固醇血症受试者进行基因分型，检测PCSK9-InsLEU多态性。主要统计分析旨在调查该变异与葡萄糖稳态/糖尿病的关联，其次是其与冠状动脉事件的关联。 结果：在该队列中，26% 的受试者被发现遗传了 PCSK9-InsLEU 变异。血脂谱没有显着差异，但与非携带者相比，InsLEU 携带者的冠状动脉事件比例显着较低（30.6% vs 22.1%，P = .04）。然而，与非携带者相比，InsLEU 携带者组中糖尿病前期和糖尿病患者的比例较高（10% vs 6%，P = .04）。因此，与非携带者相比，携带者的血浆葡萄糖浓度显着较高（5.3 vs 5.1 mmol/L，P = .02），并且更容易受到空腹血糖受损的影响（31.3% vs 14.3%，P < .01）。 结论：家族性高胆固醇血症个体携带 PCSK9-InsLEU 遗传变异，可降低冠状动脉事件的风险，但显示前驱糖尿病和糖尿病的发生率增加。鉴于这些结果，需要进一步研究以更好地了解新的 PCSK9 降低疗法的潜在长期代谢影响以及新发糖尿病的风险。 (C) 2015 年国家脂质协会。版权所有。
BACKGROUND: Recent meta-analyses have shown a dose-dependent effect of statins therapy on the increased incidence of new-onset diabetes. Proprotein convertase subtilisin/kexin type (PCSK9) inhibitors are an important group of emerging lipid-lowering therapies. PCSK9 loss-of-function mutations have been associated with low-density lipoprotein cholesterol and cardiovascular risk, but their impact on glucose homeostasis and the risk of diabetes are unclear.OBJECTIVE: We investigated the effect of PCSK9-InsLEU polymorphism on the incidence of prediabetes and diabetes.METHODS: Genotyping was performed for 724 subjects with familial hypercholesterolemia to detect the PCSK9-InsLEU polymorphism. The primary statistical analysis aimed at investigating the association of this variant with glucose homeostasis/diabetes and secondarily its association with coronary events.RESULTS: In this cohort, 26% of subjects were found to have inherited the PCSK9-InsLEU variant. No significant differences were seen in lipid profiles, but the proportion of coronary events were significantly lower in InsLEU-carriers compared with non-carriers (30.6% vs 22.1%, P = .04). However, a higher proportion of prediabetic and diabetic individuals was seen in the InsLEU-carrier group compared with non-carriers (10% vs 6%, P = .04). Accordingly, carriers had plasma glucose concentrations significantly higher (5.3 vs 5.1 mmol/L, P = .02) and were more often affected with impaired fasting glucose (31.3% vs 14.3%, P < .01) than non-carriers.CONCLUSIONS: Familial hypercholesterolemia individuals carry the PCSK9-InsLEU genetic variant benefit of lower risk of coronary events but show an increased occurrence of prediabetes and diabetes. In light of these results, further investigations are needed to better understand the potential long-term metabolic effects of the new PCSK9-lowering therapies and the risk of new-onset diabetes. (C) 2015 National Lipid Association. All rights reserved.