Møller Peter Loof, Rohde Palle D, Winther Simon, Breining Peter, Nissen Louise, Nykjaer Anders, Bøttcher Morten, Nyegaard Mette, Kjolby Mads
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
Front Cardiovasc Med. 2021 Apr 16;8:652584. doi: 10.3389/fcvm.2021.652584. eCollection 2021.
Genetic variants in the genomic region containing (encoding the protein sortilin) are strongly associated with cholesterol levels and the risk of coronary artery disease (CAD). Circulating sortilin has therefore been proposed as a potential biomarker for cardiovascular disease. Multiple studies have reported association between plasma sortilin levels and cardiovascular outcomes. However, the findings are not consistent across studies, and most studies have small sample sizes. The aim of this study was to evaluate sortilin as a biomarker for CAD in a well-characterized cohort with symptoms suggestive of CAD. In total, we enrolled 1,173 patients with suspected stable CAD referred to coronary computed tomography angiography. Sortilin was measured in plasma using two different technologies for quantifying circulating sortilin: a custom-made enzyme-linked immunosorbent assay (ELISA) and OLINK Cardiovascular Panel II. We found a relative poor correlation between the two methods (correlation coefficient = 0.21). In addition, genotyping and whole-genome sequencing were performed on all patients. By whole-genome regression analysis of sortilin levels measured with ELISA and OLINK, two independent protein quantitative trait loci (pQTL) on chromosome 1p13.3 were identified, with one of them being a well-established risk locus for CAD. Incorporating rare genetic variants from whole-genome sequence data did not identify any additional pQTLs for plasma sortilin. None of the traditional CAD risk factors, such as sex, age, smoking, and statin use, were associated with plasma sortilin levels. Furthermore, there was no association between circulating sortilin levels and coronary artery calcium score (CACS) or disease severity. Sortilin did not improve discrimination of obstructive CAD, when added to a clinical pretest probability (PTP) model for CAD. Overall, our results indicate that studies using different methodologies for measuring circulating sortilin should be compared with caution. In conclusion, the well-known risk locus for CAD is linked to lower sortilin levels in circulation, measured with ELISA; however, the effect sizes are too small for sortilin to be a useful biomarker for CAD in a clinical setting of low- to intermediate-risk chest-pain patients.
包含（编码sortilin蛋白）的基因组区域中的基因变异与胆固醇水平和冠状动脉疾病（CAD）风险密切相关。因此，循环中的sortilin被提议作为心血管疾病的潜在生物标志物。多项研究报告了血浆sortilin水平与心血管结局之间的关联。然而，各研究结果并不一致，且大多数研究样本量较小。本研究的目的是在一个具有典型CAD症状的队列中评估sortilin作为CAD生物标志物的情况。我们总共招募了1173例疑似稳定型CAD并接受冠状动脉计算机断层扫描血管造影的患者。使用两种不同的技术在血浆中测量sortilin以定量循环中的sortilin：定制的酶联免疫吸附测定（ELISA）和OLINK心血管Panel II。我们发现这两种方法之间的相关性相对较差（相关系数=0.21）。此外，对所有患者进行了基因分型和全基因组测序。通过对用ELISA和OLINK测量的sortilin水平进行全基因组回归分析，在染色体1p13.3上鉴定出两个独立的蛋白质定量性状位点（pQTL），其中一个是已确定的CAD风险位点。纳入来自全基因组序列数据的罕见基因变异并未识别出任何额外的血浆sortilin的pQTL。传统的CAD危险因素，如性别、年龄、吸烟和他汀类药物使用，均与血浆sortilin水平无关。此外，循环中的sortilin水平与冠状动脉钙化评分（CACS）或疾病严重程度之间没有关联。当将sortilin添加到CAD的临床预测试概率（PTP）模型中时，它并不能改善对阻塞性CAD的鉴别。总体而言，我们的结果表明，对于使用不同方法测量循环sortilin的研究应谨慎比较。总之，已知的CAD风险位点与用ELISA测量的循环中较低的sortilin水平相关；然而，效应大小过小，以至于在低至中度风险胸痛患者的临床环境中，sortilin无法成为有用的CAD生物标志物。
