Abstract
Genetic variants in the genomic region containing SORT1 (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 cis 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 SORT1 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.
Highlights
Coronary artery disease (CAD) is a common complex disease with a strong genetic contribution
None of the observed variation could be attributed to genetic variation as the estimates for sortilin measured with OLINK and enzyme-linked immunosorbent assay (ELISA) were h2SNP = 1.4 × 10–9 (SE = 0.23) and h2SNP = 9.4 × 10–10 (SE = 0.23), respectively
We investigated in a large well-described low- to intermediate-risk chest-pain cohort whether variation in plasma levels of soluble sortilin was under genetic influence and explored the added value of including soluble sortilin in risk stratification of patients with suspected CAD
Summary
Coronary artery disease (CAD) is a common complex disease with a strong genetic contribution. A large number of genomewide association studies (GWASs) have been conducted to identify risk loci and genes involved in the development of early onset myocardial infarction [1, 2], various aspects of atherosclerosis [3,4,5,6], and low-density lipoprotein (LDL) cholesterol levels [7,8,9,10]. The majority of LDL cholesterol–associated single-nucleotide polymorphisms (SNPs) are located in the intergenic region between PSRC1 and CELSR2, and downstream of SORT1 and MYBPHL [11]. Fine-mapping studies have found that genetic variants in the major (risk) haplotype block containing rs599834, rs646776, rs629301, and rs12740374 are associated with lower SORT1, CELSR2, and PSRC1 transcript levels in the human liver [12, 13]. It is difficult to exactly pinpoint which gene(s) is(are) responsible for the risk of developing CAD, it is believed that the CAD risk variant at 1p13.3 alters the levels of sortilin in the liver [12]
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