AUTHOR=Møller Peter Loof , Rohde Palle D. , Winther Simon , Breining Peter , Nissen Louise , Nykjaer Anders , Bøttcher Morten , Nyegaard Mette , Kjolby Mads 

TITLE=Sortilin as a Biomarker for Cardiovascular Disease Revisited

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.652584

DOI=10.3389/fcvm.2021.652584

ISSN=2297-055X

ABSTRACT=Genetic variants in the genomic region containing SORT1 (encoding sortilin) is 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 diseases. 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 coronary artery disease (CAD) in a well characterized cohort with symptoms suggestive of CAD. In total, we enrolled 1173 patients with suspected stable CAD referred to coronary Computer Tomgraphy angiography (CTA). If obstruction CAD was suspected at CTA, an invasive angiography with fractional flow reserve was performed to confirm significant disease. Sortilin was measured in plasma using two different technologies for quantifying circulating sortilin; a custom-made ELISA and OLINK Cardiovascular panel II. In addition, genotyping and genome sequencing was performed on all patients. We found a relative poor correlation between the two methods (correlation coefficient=0.24). Genome-wide association (GWAS) analysis of sortilin levels identified two protein quantitative trait loci (pQTL) on chromosome 1p13.3. Incorporating rare genetic variants from whole-genome sequence data did not identify any pQTLs for plasma sortilin. No significant effect of sex, age, smoking, statin use or other common risk factors for CAD on sortilin levels was found. Furthermore, no correlation between sortilin and coronary artery calcium score or disease severity was identified. Sortilin did not improve discrimination of obstructive CAD, when added to a clinical pre-test probability model for CAD.  Overall, our results indicate that studies using different methodologies for measuring circulating sortilin should be compared with caution. Although the SORT1 locus is a strong GWAS locus for CAD and we show that the locus drives differences in shedded circulating sortilin in plasma, however the effect size is too weak for sortilin to be a useful biomarker for CAD in a clinical setting of low-to-intermediate-risk chest-pain patients.