Mishra Pashupati P, Mishra Binisha H, Lyytikäinen Leo-Pekka, Goebeler Sirkka, Martiskainen Mika, Hakamaa Emma, Kleber Marcus E, Delgado Graciela E, März Winfried, Kähönen Mika, Karhunen Pekka J, Lehtimäki Terho
Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Am J Prev Cardiol. 2024 Oct 10;20:100884. doi: 10.1016/j.ajpc.2024.100884. eCollection 2024 Dec.
The modest added predictive value of the existing genetic risk scores (GRSs) for coronary artery disease (CAD) could be partly due to missing genetic components, hidden in the genetic architecture of intermediate phenotypes such as coronary artery calcification (CAC). In this study, we investigated the predictive ability of CAC GRS for CAD.
We investigated the association of CAC GRSs with CAD and coronary calcification among the participants in the Ludwigshafen Risk and Cardiovascular Health study (LURIC) ( = 2742), the Tampere Vascular Study (TVS) ( = 133), and the Tampere Sudden Death Study (TSDS) ( = 660) using summary data from the largest multi-ancestry GWAS meta-analysis of CAC to date. Added predictive value of the CAC GRS over the traditional CVD risk factors as well as metaGRS, a GRS for CAD constructed with 1.7 million genetic variants, was tested with standard train-test machine learning approach using the LURIC data, which had the largest sample size.
CAC GRS was significantly associated with CAD in LURIC (OR=1.41, 95 % CI [1.28-1.55]), TVS (OR=1.79, 95 % CI [1.05-3.21]) as well as in TSDS (OR=4.20, 95 % CI [1.74-10.52]). CAC GRS showed strong association with calcification areas in left (OR=1.78, 95 % CI [1.16-2.74]) and right (OR=1.71, 95 % CI [1.98-2.67]) coronary arteries. There was statistically significant added predictive value of the CAC GRS for CAD over the used traditional CVD risk factors (AUC 0.734 vs 0.717, p-value = 0.02). Furthermore, CAC GRS improved the prediction accuracy for CAD when combined with metaGRS.
This study showed that CAC GRS is a new risk marker for CAD in three European cohorts, with added predictive value over the traditional CVD risk factors.
现有冠状动脉疾病（CAD）遗传风险评分（GRS）的预测价值有限，部分原因可能是遗漏了隐藏在诸如冠状动脉钙化（CAC）等中间表型遗传结构中的遗传成分。在本研究中，我们调查了CAC GRS对CAD的预测能力。
我们利用迄今为止最大规模的多血统GWAS对CAC的荟萃分析的汇总数据，在路德维希港风险与心血管健康研究（LURIC）（n = 2742）、坦佩雷血管研究（TVS）（n = 133）和坦佩雷猝死研究（TSDS）（n = 660）的参与者中，研究了CAC GRS与CAD和冠状动脉钙化之间的关联。使用样本量最大的LURIC数据，采用标准的训练-测试机器学习方法，测试了CAC GRS相对于传统心血管疾病风险因素以及metaGRS（一种由170万个遗传变异构建的CAD GRS）的额外预测价值。
在LURIC（OR = 1.41，95%CI[1.28 - 1.55]）、TVS（OR = 1.79，95%CI[1.05 - 3.21]）以及TSDS（OR = 4.20，95%CI[1.74 - 10.52]）中，CAC GRS与CAD显著相关。CAC GRS与左冠状动脉（OR = 1.78，95%CI[1.16 - 2.74]）和右冠状动脉（OR = 1.71，95%CI[1.98 - 2.67]）的钙化面积显示出强烈关联。与所使用的传统心血管疾病风险因素相比，CAC GRS对CAD具有统计学上显著的额外预测价值（AUC 0.734对0.717，p值 = 0.02）。此外，当与metaGRS结合时，CAC GRS提高了CAD的预测准确性。
本研究表明，CAC GRS是三个欧洲队列中CAD的一种新的风险标志物，相对于传统心血管疾病风险因素具有额外的预测价值。
