Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.
Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.
复制标题
大规模代谢组分析确定了出现冠心病的新生物标志物。
DOI：
10.1371/journal.pgen.1004801
复制
发表时间：
2014-12
期刊：
影响因子：
4.5
通讯作者：
Ingelsson E
中科院分区：
文献类型：
--
作者：
Ganna A;Salihovic S;Sundström J;Broeckling CD;Hedman AK;Magnusson PK;Pedersen NL;Larsson A;Siegbahn A;Zilmer M;Prenni J;Arnlöv J;Lind L;Fall T;Ingelsson E
在大型前瞻性流行病学研究中对循环代谢物的分析可以改善对冠心病（CHD）的预测和更好的生物学理解。我们进行了一项基于质谱的非靶向代谢组学研究，以确定1，028例个体（131例事件; 10年）中CHD事件的相关性。中位随访），在1，670名个体中进行验证（282起事件; 3.9年）。中位随访）。四种代谢物重复出现，且独立于主要心血管风险因素[溶血磷脂酰胆碱18∶1（风险比[HR]/标准差[SD]增量= 0.77，P值<0.001）、溶血磷脂酰胆碱18∶2（HR = 0.81，P值<0.001）、单酸甘油酯18∶2（MG 18∶2; HR = 1.18，P值= 0.011）和鞘磷脂28∶1（HR = 0.85，P值= 0.015）]。 除了传统的风险因素外，它们共同促进了歧视和重新分类的适度改善（C统计：0.76 vs. 0.75; NRI：9.2%）。MG 18∶2与CHD的相关性与甘油三酯无关。在另外970名参与者中，溶血磷脂酰胆碱与体重指数、C-反应蛋白呈负相关，且与亚临床心血管疾病证据较少相关; MG 18∶2的模式相反。孟德尔随机化分析表明，MG 18∶2与CHD相关SNPs显著相关（与ZNF 259/APOA 5区域rs 964184相关的P值=1.2×10−7），并且对CHD有微弱但积极的因果效应（ MG 18∶2中每SD增加比值比=1.05，P值=0.05）。 总之，我们确定了四种脂质相关代谢物，有临床应用的证据，以及在冠心病发展中的因果作用。仅在过去的1-2年中，大规模人群研究的非靶向代谢组学分析才变得可行，这种无假设的代谢组学探索具有很大的潜力，可以促进冠心病（CHD）新生物标志物的发现。这些生物标志物不仅对风险分层和治疗决策很重要，而且还可以提高对心血管疾病病理生理学的理解，以确定新的药物靶点。在这项研究中，我们调查了来自三项基于人群的研究的3，600多名个体的代谢谱，并发现了四种与CHD事件相关的代谢物。我们整合了遗传和代谢组学分析来描述潜在的生物学机制，并评估新生物标志物的潜在因果效应。具体而言，我们发现一种代谢物与先前报道的与CHD相关的单核苷酸多态性密切相关，并且与孟德尔随机化分析所建议的CHD发展中的潜在因果作用一致。
Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10−7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development. Non-targeted metabolomic profiling of large population-based studies has become feasible only in the past 1–2 years and this hypothesis-free exploration of the metabolome holds a great potential to fuel the discovery of novel biomarkers for coronary heart disease (CHD). Such biomarkers are not only important for risk stratification and treatment decisions, but can also improve understanding of cardiovascular disease pathophysiology to identify new drug targets. In this study, we investigated the metabolic profiles of more than 3,600 individuals from three population-based studies, and discovered four metabolites that are consistently associated with incident CHD. We integrate genetic and metabolomic analysis to delineate the underlying biological mechanisms and evaluate potential causal effects of the novel biomarkers. Specifically, we found one metabolite to be strongly associated with single nucleotides polymorphisms previously reported for association with CHD, and consistent with a potential causal role in CHD development, as suggested by Mendelian randomization analysis.
登录
查看更多内容
影响因子：
5
作者：
Ganna, Andrea;Reilly, Marie;Ingelsson, Erik
通讯作者：
Ingelsson, Erik
DOI：
10.1152/ajpendo.1996.271.6.e1073
发表时间：
1996-12-01
影响因子：
5.1
作者：
Shamburek, RD;Zech, LA;Schwartz, CC
通讯作者：
Schwartz, CC
影响因子：
37.8
作者：
Miller, Michael;Stone, Neil J.;Pennathur, Subramanian
通讯作者：
Pennathur, Subramanian
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.
影响因子：
39.3
作者：
Magnusson, Martin;Lewis, Gregory D.;Melander, Olle
通讯作者：
Melander, Olle