Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis.
Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis.
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LPA变体与冠状动脉疾病的风险及其对脂蛋白（A）较低疗法的影响：Mendelian随机分析的影响。
DOI：
10.1001/jamacardio.2018.1470
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发表时间：
2018-07-01
期刊：
影响因子：
24
通讯作者：
European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium
中科院分区：
文献类型：
--
作者：
Burgess S;Ference BA;Staley JR;Freitag DF;Mason AM;Nielsen SF;Willeit P;Young R;Surendran P;Karthikeyan S;Bolton TR;Peters JE;Kamstrup PR;Tybjærg-Hansen A;Benn M;Langsted A;Schnohr P;Vedel-Krogh S;Kobylecki CJ;Ford I;Packard C;Trompet S;Jukema JW;Sattar N;Di Angelantonio E;Saleheen D;Howson JMM;Nordestgaard BG;Butterworth AS;Danesh J;European Prospective Investigation Into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD) Consortium
人类遗传学研究表明，血浆脂蛋白(a) (Lp[a]) 与冠心病 (CHD) 风险存在因果关系，但将 Lp(a) 水平降低 25% 至 35% 的几种疗法的随机试验并未提供任何证据表明降低 Lp(a) 水平可降低 CHD 风险。为了估计血浆 Lp(a) 水平变化的幅度，需要有与低密度脂蛋白胆固醇 (LDL-C) 水平 38.67 mg/dL（即 1 mmol/L）变化相同的与 CHD 风险相关的证据，这一变化已被证明可以产生具有临床意义的 CHD 风险降低。使用 5 项研究的个体参与者数据进行孟德尔随机化分析，并使用 48 项研究的汇总数据进行外部验证。基于人群的前瞻性队列和病例对照研究以 20 793 名 CHD 患者和 27 540 名对照者为对象，并提供个体参与者数据，而汇总数据包括 62 240 名 CHD 患者和 127 299 名对照者。分析了2016年11月至2018年3月的数据。遗传LPA评分和血浆Lp(a)质量浓度。冠心病。在纳入的研究参与者中，53% 是男性，均为欧洲白人血统，平均年龄为 57.5 岁。基因预测的 Lp(a) 与 CHD 风险的关联与 Lp(a) 浓度的绝对变化成线性比例。遗传预测 Lp(a) 浓度降低 10 mg/dL 与 CHD 风险降低 5.8% 相关（比值比 [OR], 0.942；95% CI, 0.933-0.951；P = 3 × 10−37），而使用 LDL-C 遗传评分估计的遗传预测 LDL-C 水平降低 10 mg/dL 与冠心病风险降低相关。 CHD 风险降低 14.5%（OR，0.855；95% CI，0.818-0.893；P = 2 × 10−12）。因此，Lp(a) 浓度变化 101.5 mg/dL（95% CI，71.0-137.0）与 LDL-C 水平变化 38.67 mg/dL 与 CHD 风险具有相同的关联。基因预测的 Lp(a) 浓度与 CHD 风险的关联似乎与 LDL-C 水平的变化无关，因为遗传变异模拟了他汀类药物、PCSK9 抑制剂和依折麦布与 CHD 风险之间的关系。降低 Lp(a) 的临床益处可能与 Lp(a) 浓度的绝对降低成正比。可能需要将 Lp(a) 绝对值大幅度降低约 100 mg/dL，才能产生具有临床意义的 CHD 风险降低，其降低程度与 LDL-C 水平降低 38.67 mg/dL（即 1 mmol/L）所达到的效果相似。
Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Genetic LPA score and plasma Lp(a) mass concentration. Coronary heart disease. Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10−37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10−12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).
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影响因子：
24
作者：
Ference BA;Majeed F;Penumetcha R;Flack JM;Brook RD
通讯作者：
Brook RD
影响因子：
120.7
作者：
Erqou, Sebhat;Kaptoge, Stephen;Perry, Philip L.;Di Angelantonio, Emanuele;Thompson, Alexander;White, Ian R.;Marcovina, Santica M.;Collins, Rory;Thompson, Simon G.;Danesh, John
通讯作者：
Danesh, John
影响因子：
168.9
作者：
Mihaylova, B.;Emberson, J.;Blackwell, L.;Keech, A.;Simes, J.;Barnes, E. H.;Voysey, M.;Gray, A.;Collins, R.;Baigent, C.;de Lemos, J.;Braunwald, E.;Blazing, M.;Murphy, S.;Downs, J. R.;Gotto, A.;Clearfield, M.;Holdaas, H.;Gordon, D.;Davis, B.;Koren, M.;Dahlof, B.;Poulter, N.;Sever, P.;Knopp, R. H.;Fellstrom, B.;Holdaas, H.;Jardine, A.;Schmieder, R.;Zannad, F.;Goldbourt, U.;Kaplinsky, E.;Colhoun, H. M.;Betteridge, D. J.;Durrington, P. N.;Hitman, G. A.;Fuller, J.;Neil, A.;Wanner, C.;Krane, V.;Sacks, F.;Moye, L.;Pfeffer, M.;Hawkins, C. M.;Braunwald, E.;Kjekshus, J.;Wedel, H.;Wikstrand, J.;Barter, P.;Keech, A.;Tavazzi, L.;Maggioni, A.;Marchioli, R.;Tognoni, G.;Franzosi, M. G.;Maggioni, A.;Bloomfield, H.;Robins, S.;Collins, R.;Armitage, J.;Keech, A.;Parish, S.;Peto, R.;Sleight, P.;Pedersen, T. R.;Ridker, P. M.;Holman, R.;Meade, T.;Simes, J.;Keech, A.;MacMahon, S.;Marschner, I.;Tonkin, A.;Shaw, J.;Serruys, P. W.;Nakamura, H.;Knatterud, G.;Furberg, C.;Byington, R.;Macfarlane, P.;Cobbe, S.;Ford, I.;Murphy, M.;Blauw, G. J.;Packard, C.;Shepherd, J.;Kjekshus, J.;Pedersen, T.;Wilhelmsen, L.;Braunwald, E.;Cannon, C.;Murphy, S.;Collins, R.;Armitage, J.;Bowman, L.;Parish, S.;Peto, R.;Sleight, P.;Baigent, C.;Landray, M.;Collins, R.;La Rosa, J.;Rossouw, J.;Probstfield, J.;Shepherd, J.;Cobbe, S.;Macfarlane, P.;Ford, I.
通讯作者：
Ford, I.
影响因子：
39.3
作者：
Nordestgaard BG;Chapman MJ;Ray K;Borén J;Andreotti F;Watts GF;Ginsberg H;Amarenco P;Catapano A;Descamps OS;Fisher E;Kovanen PT;Kuivenhoven JA;Lesnik P;Masana L;Reiner Z;Taskinen MR;Tokgözoglu L;Tybjærg-Hansen A;European Atherosclerosis Society Consensus Panel
通讯作者：
European Atherosclerosis Society Consensus Panel
影响因子：
15.9
作者：
BOERWINKLE, E;LEFFERT, CC;HOBBS, HH
通讯作者：
HOBBS, HH