Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study.
Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study.
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DOI：
10.1016/j.jacc.2015.02.020
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发表时间：
2015-04-21
影响因子：
24
通讯作者：
Brook RD
中科院分区：
文献类型：
--
作者：
Ference BA;Majeed F;Penumetcha R;Flack JM;Brook RD
通过用依zetimibe单独或与3-羟基-3-甲基戊二酰辅酶a还原酶（HMGCR）抑制剂（他汀类药物）抑制Niemann-Pick C1-Like 1 （NPC1L1）受体降低低密度脂蛋白胆固醇（LDL-C）是否会降低冠心病（CHD）的风险存在相当大的不确定性。本研究评估了由NPC1L1基因（依zetimibe的靶点）、HMGCR基因（他汀类药物的靶点）或两者（联合治疗的靶点）多态性介导的自然随机分配降低LDL-C对冠心病风险的影响。我们构建了NPC1L1和HMGCR遗传LDL-C评分，将参与者自然随机分为4组：参考组、NPC1L1多态性介导的低LDL-C、HMGCR多态性介导的低LDL-C、NPC1L1和HMGCR多态性介导的低LDL-C。我们采用2 × 2因子孟德尔随机化研究设计比较各组冠心病（致死性或非致死性心肌梗死）的风险。共纳入来自14项研究的108376人（10464例冠心病事件）。4组间基线特征无显著性差异，证实随机分配。与对照组相比，NPC1L1组LDL-C降低2.4 mg/dl，冠心病风险降低4.8%（比值比[OR]: 0.952, 95%可信区间[CI]: 0.920 ~ 0.985）；而HMGCR组LDL-C降低了2.9 mg/dl，冠心病的风险也降低了5.3% （OR: 0.947, 95% CI: 0.909 ~ 0.986）。由NPC1L1和HMGCR多态性介导的低LDL-C组LDL-C加性降低5.8 mg/dl，冠心病风险加性降低10.8% （OR: 0.892, 95% CI: 0.854 ~ 0.932）。低LDL-C对由NPC1L1、HMGCR或两者多态性介导的冠心病风险的影响在单位低LDL-C下大致相同，且与低LDL-C绝对暴露成对数线性正比。
Considerable uncertainty exists as to whether lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor with ezetimibe, either alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (statin), will reduce the risk of coronary heart disease (CHD). This study evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins), or both (target of combination therapy) on the risk of CHD. We constructed NPC1L1 and HMGCR genetic LDL-C scores to naturally randomize participants into 4 groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by polymorphisms in both NPC1L1 and HMGCR. We compared the risk of CHD (fatal or nonfatal myocardial infarction) among each group using a 2 × 2 factorial mendelian randomization study design. A total of 108,376 persons (10,464 CHD events) from 14 studies were included. There were no significant differences in baseline characteristics among the 4 groups, thus confirming that allocation was random. Compared to the reference group, the NPC1L1 group had 2.4 mg/dl lower LDL-C and 4.8% lower risk of CHD (odds ratio [OR]: 0.952, 95% confidence interval [CI]: 0.920 to 0.985); whereas the HMGCR group had 2.9 mg/dl lower LDL-C and a similar 5.3% lower risk of CHD (OR: 0.947, 95% CI: 0.909 to 0.986). The group with lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms had 5.8 mg/dl additively lower LDL-C and a 10.8% log-linearly additive lower risk of CHD (OR: 0.892, 95% CI: 0.854 to 0.932). The effect of lower LDL-C on the risk of CHD mediated by polymorphisms in NPC1L1, HMGCR, or both is approximately the same per unit lower LDL-C and log-linearly proportional to the absolute exposure to lower LDL-C.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
与人类血液低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯相关的六个新位点。
影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1056/nejmoa1001282
发表时间：
2010-04-29
期刊：
The New England journal of medicine
影响因子：
--
作者：
ACCORD Study Group;Ginsberg HN;Elam MB;Lovato LC;Crouse JR 3rd;Leiter LA;Linz P;Friedewald WT;Buse JB;Gerstein HC;Probstfield J;Grimm RH;Ismail-Beigi F;Bigger JT;Goff DC Jr;Cushman WC;Simons-Morton DG;Byington RP
通讯作者：
Byington RP
影响因子：
30.8
作者：
Deloukas, Panos;Kanoni, Stavroula;Willenborg, Christina;Farrall, Martin;Assimes, Themistocles L.;Thompson, John R.;Ingelsson, Erik;Saleheen, Danish;Erdmann, Jeanette;Goldstein, Benjamin A.;Stirrups, Kathleen;Koenig, Inke R.;Cazier, Jean-Baptiste;Johansson, Asa;Hall, Alistair S.;Lee, Jong-Young;Willer, Cristen J.;Chambers, John C.;Esko, Tonu;Folkersen, Lasse;Goel, Anuj;Grundberg, Elin;Havulinna, Aki S.;Ho, Weang K.;Hopewell, Jemma C.;Eriksson, Niclas;Kleber, Marcus E.;Kristiansson, Kati;Lundmark, Per;Lyytikainen, Leo-Pekka;Rafelt, Suzanne;Shungin, Dmitry;Strawbridge, Rona J.;Thorleifsson, Gudmar;Tikkanen, Emmi;Van Zuydam, Natalie;Voight, Benjamin F.;Waite, Lindsay L.;Zhang, Weihua;Ziegler, Andreas;Absher, Devin;Altshuler, David;Balmforth, Anthony J.;Barroso, Ines;Braund, Peter S.;Burgdorf, Christof;Claudi-Boehm, Simone;Cox, David;Dimitriou, Maria;Do, Ron;Doney, Alex S. F.;El Mokhtari, NourEddine;Eriksson, Per;Fischer, Krista;Fontanillas, Pierre;Franco-Cereceda, Anders;Gigante, Bruna;Groop, Leif;Gustafsson, Stefan;Hager, Joerg;Hallmans, Goran;Han, Bok-Ghee;Hunt, Sarah E.;Kang, Hyun M.;Illig, Thomas;Kessler, Thorsten;Knowles, Joshua W.;Kolovou, Genovefa;Kuusisto, Johanna;Langenberg, Claudia;Langford, Cordelia;Leander, Karin;Lokki, Marja-Liisa;Lundmark, Anders;McCarthy, Mark I.;Meisinger, Christa;Melander, Olle;Mihailov, Evelin;Maouche, Seraya;Morris, Andrew D.;Mueller-Nurasyid, Martina;Nikus, Kjell;Peden, John F.;Rayner, N. William;Rasheed, Asif;Rosinger, Silke;Rubin, Diana;Rumpf, Moritz P.;Schaefer, Arne;Sivananthan, Mohan;Song, Ci;Stewart, Alexandre F. R.;Tan, Sian-Tsung;Thorgeirsson, Gudmundur;van der Schoot, C. Ellen;Wagner, Peter J.;Wells, George A.;Wild, Philipp S.;Yang, Tsun-Po;Amouyel, Philippe;Arveiler, Dominique;Basart, Hanneke;Boehnke, Michael;Boerwinkle, Eric;Brambilla, Paolo;Cambien, Francois;Cupples, Adrienne L.;de Faire, Ulf;Dehghan, Abbas;Diemert, Patrick;Epstein, Stephen E.;Evans, Alun;Ferrario, Marco M.;Ferrieres, Jean;Gauguier, Dominique;Go, Alan S.;Goodall, Alison H.;Gudnason, Villi;Hazen, Stanley L.;Holm, Hilma;Iribarren, Carlos;Jang, Yangsoo;Kahonen, Mika;Kee, Frank;Kim, Hyo-Soo;Klopp, Norman;Koenig, Wolfgang;Kratzer, Wolfgang;Kuulasmaa, Kari;Laakso, Markku;Laaksonen, Reijo;Lee, Ji-Young;Lind, Lars;Ouwehand, Willem H.;Parish, Sarah;Park, Jeong E.;Pedersen, Nancy L.;Peters, Annette;Quertermous, Thomas;Rader, Daniel J.;Salomaa, Veikko;Schadt, Eric;Shah, Svati H.;Sinisalo, Juha;Stark, Klaus;Stefansson, Kari;Tregouet, David-Alexandre;Virtamo, Jarmo;Wallentin, Lars;Wareham, Nicholas;Zimmermann, Martina E.;Nieminen, Markku S.;Hengstenberg, Christian;Sandhu, Manjinder S.;Pastinen, Tomi;Syvanen, Ann-Christine;Hovingh, G. Kees;Dedoussis, George;Franks, Paul W.;Lehtimaki, Terho;Metspalu, Andres;Zalloua, Pierre A.;Siegbahn, Agneta;Schreiber, Stefan;Ripatti, Samuli;Blankenberg, Stefan S.;Perola, Markus;Clarke, Robert;Boehm, Bernhard O.;O'Donnell, Christopher;Reilly, Muredach P.;Maerz, Winfried;Collins, Rory;Kathiresan, Sekar;Hamsten, Anders;Kooner, Jaspal S.;Thorsteinsdottir, Unnur;Danesh, John;Palmer, Colin N. A.;Roberts, Robert;Watkins, Hugh;Schunkert, Heribert;Samani, Nilesh J.
通讯作者：
Samani, Nilesh J.