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ACLY和心血管疾病的孟德尔随机化研究
Mendelian Randomization Study of ACLY and Cardiovascular Disease


Brian A. Ference ... 心脑血管疾病 • 2019.03.14
相关阅读
• bempedoic acid降低低密度脂蛋白胆固醇的安全性和疗效

摘要


背景

ATP柠檬酸裂合酶是3-羟基-3-甲戊二酸辅酶A还原酶(HMGCR)上游胆固醇生物合成途径中的一种酶,而HMGCR是他汀类药物的靶点。基因抑制ATP柠檬酸裂合酶是否与有害结局相关尚不清楚,在低密度脂蛋白(LDL胆固醇水平的每单位降幅下,是否与基因抑制HMGCR具有相同的效应亦不清楚。

 

方法

我们构建了由ATP柠檬酸裂合酶编码基因(ACLY)和HMGCR编码基因的独立遗传性变异体组成的基因评分,以创建分别模拟ATP柠檬酸裂合酶抑制剂和HMGCR抑制剂(他汀类药物)效应的工具。然后我们比较了这些基因评分与血脂水平、脂蛋白水平以及心血管事件和癌症风险之间的关联。

 

结果

共有654,783例参与者(包括有主要心血管事件的105,429例参与者)被纳入本研究。ACLYHMGCR评分与相似的血脂和脂蛋白水平变化模式相关,并且LDL胆固醇水平每降低10 mg/dL,两个评分对心血管事件风险产生的效应相似:对于ACLY评分和HMGCR评分,心血管事件的比值比分别为0.823(95%置信区间[CI],0.78~0.87;P=4.0×1014)和0.836(95% CI,0.81~0.87;P=3.9×1019)。不论是对ATP柠檬酸裂合酶的终生基因抑制,还是对HMGCR的终生基因抑制,均与癌症风险增加无关。

 

结论

模拟ATP柠檬酸裂合酶抑制剂和他汀类药物效应的基因变异体似乎通过相同的作用机制降低血浆LDL胆固醇水平,并且在LDL胆固醇水平的每单位降幅下,两者对心血管疾病风险的效应相似(由Esperion Therapeutics等资助)。





作者信息

Brian A. Ference, M.D., Kausik K. Ray, M.D., Alberico L. Catapano, Ph.D., Thatcher B. Ference, Stephen Burgess, Ph.D., David R. Neff, D.O., Clare Oliver-Williams, Ph.D., Angela M. Wood, Ph.D., Adam S. Butterworth, Ph.D., Emanuele Di Angelantonio, M.D., John Danesh, D.Phil., John J.P. Kastelein, M.D., Ph.D., and Stephen J. Nicholls, M.B., B.S., Ph.D.
From the Centre for Naturally Randomized Trials (B.A.F., T.B.F.), Medical Research Council, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (B.A.F., S.B., C.O.-W., A.M.W., A.S.B., E.D.A., J.D.), Medical Research Council Biostatistics Unit (S.B.), and NIHR Blood and Transplant Research Unit in Donor Health and Genomics (A.S.B., E.D.A., J.D.), University of Cambridge, Cambridge, and Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London (K.K.R.) — all in the United Kingdom; the Department of Pharmacologic and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Milan (A.L.C.); Michigan State University, East Lansing (D.R.N.); the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); and Monash University, Clayton, VIC, Australia (S.J.N.). Address reprint requests to Dr. Brian A. Ference at the Centre for Naturally Randomized Trials, University of Cambridge, 2 Worts’ Causeway, Cambridge CB1 8RN, United Kingdom, or at baf29@medschl.cam.ac.uk.

 

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