全基因组测序揭示了冠状动脉钙化的两个基因座，并确定ARSE为血管钙化的调节因子。
Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.
作者信息
de Vries Paul S, Conomos Matthew P, Singh Kuldeep, Nicholson Christopher J, Jain Deepti, Hasbani Natalie R, Jiang Wanlin, Lee Sujin, Lino Cardenas Christian L, Lutz Sharon M, Wong Doris, Guo Xiuqing, Yao Jie, Young Erica P, Tcheandjieu Catherine, Hilliard Austin T, Bis Joshua C, Bielak Lawrence F, Brown Michael R, Musharoff Shaila, Clarke Shoa L, Terry James G, Palmer Nicholette D, Yanek Lisa R, Xu Huichun, Heard-Costa Nancy, Wessel Jennifer, Selvaraj Margaret Sunitha, Li Rebecca H, Sun Xiao, Turner Adam W, Stilp Adrienne M, Khan Alyna, Newman Anne B, Rasheed Asif, Freedman Barry I, Kral Brian G, McHugh Caitlin P, Hodonsky Chani, Saleheen Danish, Herrington David M, Jacobs David R, Nickerson Deborah A, Boerwinkle Eric, Wang Fei Fei, Heiss Gerardo, Jun Goo, Kinney Greg L, Sigurslid Haakon H, Doddapaneni HarshaVardhan, Hall Ira M, Bensenor Isabela M, Broome Jai, Crapo James D, Wilson James G, Smith Jennifer A, Blangero John, Vargas Jose D, Mosquera Jose Verdezoto, Smith Joshua D, Viaud-Martinez Karine A, Ryan Kathleen A, Young Kendra A, Taylor Kent D, Lange Leslie A, Emery Leslie S, Bittencourt Marcio S, Budoff Matthew J, Montasser May E, Yu Miao, Mahaney Michael C, Mahamdeh Mohammed S, Fornage Myriam, Franceschini Nora, Lotufo Paulo A, Natarajan Pradeep, Wong Quenna, Mathias Rasika A, Gibbs Richard A, Do Ron, Mehran Roxana, Tracy Russell P, Kim Ryan W, Nelson Sarah C, Damrauer Scott M, Kardia Sharon L R, Rich Stephen S, Fuster Valentin, Napolioni Valerio, Zhao Wei, Tian Wenjie, Yin Xianyong, Min Yuan-I, Manning Alisa K, Peloso Gina, Kelly Tanika N, O'Donnell Christopher J, Morrison Alanna C, Curran Joanne E, Zapol Warren M, Bowden Donald W, Becker Lewis C, Correa Adolfo, Mitchell Braxton D, Psaty Bruce M, Carr John Jeffrey, Pereira Alexandre C, Assimes Themistocles L, Stitziel Nathan O, Hokanson John E, Laurie Cecelia A, Rotter Jerome I, Vasan Ramachandran S, Post Wendy S, Peyser Patricia A, Miller Clint L, Malhotra Rajeev
机构信息
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Genetic Analysis Center, Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
出版信息
Nat Cardiovasc Res. 2023 Dec;2(12):1159-1172. doi: 10.1038/s44161-023-00375-y. Epub 2023 Dec 4.
Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( and ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of and in human vascular smooth muscle cells (VSMCs) demonstrate that is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near with reduced CAC is likely explained by reduced expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.
冠状动脉钙化（CAC）是动脉粥样硬化的一种度量，也是冠状动脉疾病（CAD）事件的一个公认的预测指标。在此，我们描述了一项针对来自多个祖先群体的22400名参与者的CAC全基因组关联研究（GWAS）。我们证实了与四个已知基因座的关联，并确定了另外两个与CAC相关的基因座（和），在对两个新基因座的重复分析中均有显著关联的证据。在人血管平滑肌细胞（VSMC）中对和进行的功能测定表明，是VSMC钙化以及VSMC表型从收缩型转变为钙化或成骨型的一个促进因子。此外，我们表明，与CAC降低相关的基因座附近变异的关联可能是由于增强子变异rs5982944的G等位基因导致表达降低所致。我们的研究强调了ARSE是动脉粥样硬化性血管钙化的一个重要促成因素，也是血管钙化疾病的一个潜在药物靶点。
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