Natarajan Pradeep, Bis Joshua C, Bielak Lawrence F, Cox Amanda J, Dörr Marcus, Feitosa Mary F, Franceschini Nora, Guo Xiuqing, Hwang Shih-Jen, Isaacs Aaron, Jhun Min A, Kavousi Maryam, Li-Gao Ruifang, Lyytikäinen Leo-Pekka, Marioni Riccardo E, Schminke Ulf, Stitziel Nathan O, Tada Hayato, van Setten Jessica, Smith Albert V, Vojinovic Dina, Yanek Lisa R, Yao Jie, Yerges-Armstrong Laura M, Amin Najaf, Baber Usman, Borecki Ingrid B, Carr J Jeffrey, Chen Yii-Der Ida, Cupples L Adrienne, de Jong Pim A, de Koning Harry, de Vos Bob D, Demirkan Ayse, Fuster Valentin, Franco Oscar H, Goodarzi Mark O, Harris Tamara B, Heckbert Susan R, Heiss Gerardo, Hoffmann Udo, Hofman Albert, Išgum Ivana, Jukema J Wouter, Kähönen Mika, Kardia Sharon L R, Kral Brian G, Launer Lenore J, Massaro Joe, Mehran Roxana, Mitchell Braxton D, Mosley Thomas H, de Mutsert Renée, Newman Anne B, Nguyen Khanh-Dung, North Kari E, O'Connell Jeffrey R, Oudkerk Matthijs, Pankow James S, Peloso Gina M, Post Wendy, Province Michael A, Raffield Laura M, Raitakari Olli T, Reilly Dermot F, Rivadeneira Fernando, Rosendaal Frits, Sartori Samantha, Taylor Kent D, Teumer Alexander, Trompet Stella, Turner Stephen T, Uitterlinden Andre G, Vaidya Dhananjay, van der Lugt Aad, Völker Uwe, Wardlaw Joanna M, Wassel Christina L, Weiss Stefan, Wojczynski Mary K, Becker Diane M, Becker Lewis C, Boerwinkle Eric, Bowden Donald W, Deary Ian J, Dehghan Abbas, Felix Stephan B, Gudnason Vilmundur, Lehtimäki Terho, Mathias Rasika, Mook-Kanamori Dennis O, Psaty Bruce M, Rader Daniel J, Rotter Jerome I, Wilson James G, van Duijn Cornelia M, Völzke Henry, Kathiresan Sekar, Peyser Patricia A, O'Donnell Christopher J
Circ Cardiovasc Genet. 2016 Dec;9(6):511-520. doi: 10.1161/CIRCGENETICS.116.001572. Epub 2016 Nov 21.
The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease.
We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3×10). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10) and 1.4% reduced carotid intima-media thickness (P=4×10) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1×10).
Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.
无症状个体中亚临床动脉粥样硬化的负担具有遗传性，且与临床冠心病发生风险升高相关。我们试图鉴定蛋白质编码区域中与亚临床动脉粥样硬化及后续冠心病风险相关的基因变异。
我们在CHARGE联盟（基因组流行病学心脏与衰老研究队列）中，共研究了25109名通过心脏计算机断层扫描测量冠状动脉钙化（CAC）的欧洲血统和非洲血统参与者，以及52869名通过超声测量颈总动脉内膜中层厚度的参与者。对参与者进行全基因组247870个DNA序列变异（外显子中有231539个）的基因分型。对各队列的CAC和颈动脉内膜中层厚度进行全外显子组关联研究的荟萃分析。载脂蛋白B（APOB）的p.Arg3527Gln变异与CAC增加4倍相关（P = 3×10）。与非携带者相比，载脂蛋白E（APOE）的ε2等位基因（p.Arg176Cys）与CAC降低22.3%（P = 1×10）和颈动脉内膜中层厚度降低1.4%（P = 4×10）均相关。在以低密度脂蛋白胆固醇浓度为条件的二次分析中，ε2与CAC的保护关联虽有所减弱，但仍具有高度显著性。此外，ε2的存在与冠心病风险降低相关（比值比0.77；P = 1×10）。
全外显子组关联荟萃分析表明，APOB和APOE中的蛋白质编码变异与亚临床动脉粥样硬化相关。APOE ε2代表了首个在多个种族中与多种亚临床动脉粥样硬化特征以及临床冠心病均存在显著关联的基因。
