对超过30万人的血浆脂质进行全外显子组关联研究。
Exome-wide association study of plasma lipids in >300,000 individuals.
作者信息
Liu Dajiang J, Peloso Gina M, Yu Haojie, Butterworth Adam S, Wang Xiao, Mahajan Anubha, Saleheen Danish, Emdin Connor, Alam Dewan, Alves Alexessander Couto, Amouyel Philippe, Di Angelantonio Emanuele, Arveiler Dominique, Assimes Themistocles L, Auer Paul L, Baber Usman, Ballantyne Christie M, Bang Lia E, Benn Marianne, Bis Joshua C, Boehnke Michael, Boerwinkle Eric, Bork-Jensen Jette, Bottinger Erwin P, Brandslund Ivan, Brown Morris, Busonero Fabio, Caulfield Mark J, Chambers John C, Chasman Daniel I, Chen Y Eugene, Chen Yii-Der Ida, Chowdhury Rajiv, Christensen Cramer, Chu Audrey Y, Connell John M, Cucca Francesco, Cupples L Adrienne, Damrauer Scott M, Davies Gail, Deary Ian J, Dedoussis George, Denny Joshua C, Dominiczak Anna, Dubé Marie-Pierre, Ebeling Tapani, Eiriksdottir Gudny, Esko Tõnu, Farmaki Aliki-Eleni, Feitosa Mary F, Ferrario Marco, Ferrieres Jean, Ford Ian, Fornage Myriam, Franks Paul W, Frayling Timothy M, Frikke-Schmidt Ruth, Fritsche Lars G, Frossard Philippe, Fuster Valentin, Ganesh Santhi K, Gao Wei, Garcia Melissa E, Gieger Christian, Giulianini Franco, Goodarzi Mark O, Grallert Harald, Grarup Niels, Groop Leif, Grove Megan L, Gudnason Vilmundur, Hansen Torben, Harris Tamara B, Hayward Caroline, Hirschhorn Joel N, Holmen Oddgeir L, Huffman Jennifer, Huo Yong, Hveem Kristian, Jabeen Sehrish, Jackson Anne U, Jakobsdottir Johanna, Jarvelin Marjo-Riitta, Jensen Gorm B, Jørgensen Marit E, Jukema J Wouter, Justesen Johanne M, Kamstrup Pia R, Kanoni Stavroula, Karpe Fredrik, Kee Frank, Khera Amit V, Klarin Derek, Koistinen Heikki A, Kooner Jaspal S, Kooperberg Charles, Kuulasmaa Kari, Kuusisto Johanna, Laakso Markku, Lakka Timo, Langenberg Claudia, Langsted Anne, Launer Lenore J, Lauritzen Torsten, Liewald David C M, Lin Li An, Linneberg Allan, Loos Ruth J F, Lu Yingchang, Lu Xiangfeng, Mägi Reedik, Malarstig Anders, Manichaikul Ani, Manning Alisa K, Mäntyselkä Pekka, Marouli Eirini, Masca Nicholas G D, Maschio Andrea, Meigs James B, Melander Olle, Metspalu Andres, Morris Andrew P, Morrison Alanna C, Mulas Antonella, Müller-Nurasyid Martina, Munroe Patricia B, Neville Matt J, Nielsen Jonas B, Nielsen Sune F, Nordestgaard Børge G, Ordovas Jose M, Mehran Roxana, O'Donnell Christoper J, Orho-Melander Marju, Molony Cliona M, Muntendam Pieter, Padmanabhan Sandosh, Palmer Colin N A, Pasko Dorota, Patel Aniruddh P, Pedersen Oluf, Perola Markus, Peters Annette, Pisinger Charlotta, Pistis Giorgio, Polasek Ozren, Poulter Neil, Psaty Bruce M, Rader Daniel J, Rasheed Asif, Rauramaa Rainer, Reilly Dermot F, Reiner Alex P, Renström Frida, Rich Stephen S, Ridker Paul M, Rioux John D, Robertson Neil R, Roden Dan M, Rotter Jerome I, Rudan Igor, Salomaa Veikko, Samani Nilesh J, Sanna Serena, Sattar Naveed, Schmidt Ellen M, Scott Robert A, Sever Peter, Sevilla Raquel S, Shaffer Christian M, Sim Xueling, Sivapalaratnam Suthesh, Small Kerrin S, Smith Albert V, Smith Blair H, Somayajula Sangeetha, Southam Lorraine, Spector Timothy D, Speliotes Elizabeth K, Starr John M, Stirrups Kathleen E, Stitziel Nathan, Strauch Konstantin, Stringham Heather M, Surendran Praveen, Tada Hayato, Tall Alan R, Tang Hua, Tardif Jean-Claude, Taylor Kent D, Trompet Stella, Tsao Philip S, Tuomilehto Jaakko, Tybjaerg-Hansen Anne, van Zuydam Natalie R, Varbo Anette, Varga Tibor V, Virtamo Jarmo, Waldenberger Melanie, Wang Nan, Wareham Nick J, Warren Helen R, Weeke Peter E, Weinstock Joshua, Wessel Jennifer, Wilson James G, Wilson Peter W F, Xu Ming, Yaghootkar Hanieh, Young Robin, Zeggini Eleftheria, Zhang He, Zheng Neil S, Zhang Weihua, Zhang Yan, Zhou Wei, Zhou Yanhua, Zoledziewska Magdalena, Howson Joanna M M, Danesh John, McCarthy Mark I, Cowan Chad A, Abecasis Goncalo, Deloukas Panos, Musunuru Kiran, Willer Cristen J, Kathiresan Sekar
机构信息
Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA.
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
出版信息
Nat Genet. 2017 Dec;49(12):1758-1766. doi: 10.1038/ng.3977. Epub 2017 Oct 30.
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
我们在超过30万名参与者中对聚焦外显子组的基因分型阵列上的变异进行了筛选（在超过28万名参与者中进行了重复验证），并在250个位点鉴定出444个与总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）和/或甘油三酯（TG）显著相关的独立变异。在两个位点（JAK2和A1CF），对小鼠进行的实验分析显示脂质变化与人类数据一致。我们还发现：（i）β地中海贫血性状携带者的TC较低，且对冠状动脉疾病（CAD）具有保护作用；（ii）排除CETP位点后，血浆HDL-C与年龄相关性黄斑变性风险之间不存在可预测的关系；（iii）仅某些降低LDL-C的机制似乎会增加2型糖尿病（T2D）的风险；（iv）参与富含TG脂蛋白肝脏生成的降低TG等位基因（TM6SF2和PNPLA3）与较高的肝脏脂肪、较高的T2D风险和较低的CAD风险相关，而参与外周脂肪分解的降低TG等位基因（LPL和ANGPTL4）对肝脏脂肪没有影响，但降低了T2D和CAD的风险。
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