Abstract

RNA modification plays important roles in many biological processes such as gene expression control. Genetic variants that affect RNA modification may have functional roles in aortic dissection. The aim of this study was to identify RNA modifications related to spontaneous coronary artery dissection (SCAD). We examined the association of RNA modification-associated single-nucleotide polymorphisms (RNAm-SNPs) with SCAD in summary data from a genome-wide association study (GWAS) of European descent (270 SCAD cases and 5,263 controls). Furthermore, we performed expression quantitative loci (eQTL) and protein quantitative loci (pQTL) analyses for the RNAm-SNPs using publicly available data. Functional enrichment and protein–protein interaction analyses were performed for the identified proteins. We found 11,464 unique RNAm-SNPs in the SCAD GWAS dataset, and 519 were nominally associated with SCAD. Nine RNAm-SNPs were associated with SCAD at p < 0.001, and among them, seven were N6-methyladenosine (m6A) methylation-related SNPs, one (rs113664950 in HLA-DQB1) was m7G-associated SNP, and one [rs580060 in the 3′-UTR of Mitochondrial Ribosomal Protein S21 (MRPS21)] was A-to-I modification SNP. The genome-wide significant SNP rs3818978 (SCAD association p = 5.74 × 10–10) in the 5′-UTR of MRPS21 was related to m6A modification. These nine SNPs all showed eQTL effects, and six of them were associated with circulating protein or metabolite levels. The related protein-coding genes were enriched in specific Gene Ontology (GO) terms such as extracellular space, extracellular region, defense response, lymphocyte migration, receptor binding and cytokine receptor binding, and so on. The present study found the associations between RNAm-SNPs and SCAD. The findings suggested that RNA modification may play functional roles in SCAD.

Highlights

  • Aortic dissections (ADs) are complex disorders affecting the aorta

  • This study showed that spontaneous coronary artery dissection (SCAD)-associated SNPs identified in genome-wide association study (GWAS) were related to RNA modification

  • This study found SCAD-associated RNAm-SNPs and suggested that RNA modification may play important roles in SCAD

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Summary

Introduction

Aortic dissections (ADs) are complex disorders affecting the aorta. Typically, ADs begin with a tear in the aortic intima, and blood will intrude into the aortic media and separate the mid-membrane, separating a true from a false lumen. Aortic dissection can be inherited, and genetic factors were involved. AD is a heterogeneous disease that can occur in association with syndromes (e.g., Marfan syndrome, Loeys– Dietz aortic aneurysm syndrome) genetically predisposed to AD (Finkbohner et al, 1995; van Karnebeek et al, 2001). Previous studies focused on the syndromes due to variations of TGFBR2 gene have confirmed the abnormality of the transforming growth factor-beta (TGF-β) pathway regulation as a mechanism contributing to aneurysm formation. Genetic studies have demonstrated that ADs occur in familial aggregates and have identified many genetic loci for this disease (LeMaire et al, 2011; Guo et al, 2016; van ’t Hof et al, 2016; Turley et al, 2020).

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