Genome-Wide Identification of Associations of Circulating Molecules With Spontaneous Coronary Artery Dissection and Aortic Aneurysm and Dissection

Abstract

Circulating proteins play functional roles in various biological processes and disease pathogenesis. The aim of this study was to highlight circulating proteins associated with aortic aneurysm and dissection (AAD) and spontaneous coronary artery dissection (SCAD). We examined the associations of circulating molecule levels with SCAD by integrating data from a genome-wide association study (GWAS) of CanSCAD and 7 pQTL studies. Mendelian randomization (MR) analysis was applied to examine the associations between circulating molecule levels and AAD by using data from UK Biobank GWAS and pQTL studies. The SCAD-associated SNPs in 1q21.2 were strongly associated with circulating levels of extracellular matrix protein 1 (ECM1) and 25 other proteins (encoded by CTSS, CAT, CNDP1, KNG1, SLAMF7, TIE1, CXCL1, MBL2, ESD, CXCL16, CCL14, KCNE5, CST7, PSME1, GPC3, MAP2K4, SPOCK3, LRPPRC, CLEC4M, NOG, C1QTNF9, CX3CL1, SCP2D1, SERPINF2, and FN1). These proteins were enriched in biological processes such as regulation of peptidase activity and regulation of cellular protein metabolic processes. Proteins (FGF6, FGF9, HGF, BCL2L1, and VEGFA) involved in the Ras signaling pathway were identified to be related to AAD. In addition, SCAD- and AAD-associated SNPs were associated with cytokine and lipid levels. MR analysis showed that circulating ECM1, SPOCK3 and IL1b levels were associated with AAD. Circulating levels of low-density lipoprotein cholesterol and small very-low-density lipoprotein particles were strongly associated with AAD. The present study found associations between circulating proteins and lipids and SCAD and AAD. Circulating ECM1 and low-density lipoprotein cholesterol may play a role in the pathology of SCAD and AAD.

The genetics of spontaneous coronary artery dissection: a scoping review

“…These attempts have indicated some chromosomal associations with SCAD presentation, including in 1q21.2, 6p24.1, 12q13.312q13.3, and 21q22.11 and five genetic loci ( PHACTR1 , LRP1 , LINC00310 , and FBN1 ) 114,116 . In line with this finding, another report supported that genetic variants in 1q21.2 may affect SCAD risk by its regulatory effects in protein expression in related tissues 119 . Although the clinical significance of these findings remains to be elucidated, this opens a new pathway for identifying the pathogenesis of SCAD.…”

“…114,116 In line with this finding, another report supported that genetic variants in 1q21.2 may affect SCAD risk by its regulatory effects in protein expression in related tissues. 119 Although the clinical significance of these findings remains to be elucidated, this opens a new pathway for identifying the pathogenesis of SCAD.…”

Sex, Racial, and Ethnic Disparities in Acute Coronary Syndrome: Novel Risk Factors and Recommendations for Earlier Diagnosis to Improve Outcomes

“…Additionally, SCAD-associated single-nucleotide polymorphisms were associated with levels of 42 circulating cytokines including IL (interleukin)-10, IL-12p70, IL-13, IL-7, vascular endothelial growth factor, and 85 metabolites including low-density lipoprotein cholesterol (LDL-C). 16…”

Applying multi-omics techniques to the discovery of biomarkers for acute aortic dissection

“…Additionally, it has been discovered that many lipid-related proteins, including the carboxypeptidase N catalytic chain proteins (CPNs), complement component proteins, serum amyloid A protein (SAA), and complement component proteins, are differentially expressed in AAD ( 135 ). Circulating levels of LDL cholesterol and very low density lipoprotein (VLDL) small particles are also strongly linked to AAD ( 136 ).…”