7 research outputs found
Spontaneous Coronary Artery Dissection
Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of non-atherosclerotic acute coronary syndromes leading to myocardial infarction. It is characterised by the presence of blood entering and separating the layers of the coronary arterial wall to form a false lumen. This leads to external compression of the true coronary lumen restricting coronary blood flow and leading to coronary insufficiency (Figure 1). SCAD should be distinguished from atherosclerotic dissections arising from plaque rupture events or erosions allowing blood to enter the intimal space and from iatrogenic dissections arising during coronary procedures
Editorial on "Characteristics of extension and de novo recurrent spontaneous coronary artery dissection".
Editorial on "Characteristics of extension and de novo recurrent spontaneous coronary artery dissection"
Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation from Genome Sequencing
Background - Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disorders, have been implicated; however, the genetic architecture is poorly understood. Here, we aim to better understand the diagnostic yield of rare variant genetic testing among a cohort of SCAD survivors and to identify genes or gene-sets that have a significant enrichment of rare variants.Methods - We sequenced a cohort of 384 SCAD survivors from the UK, alongside 13,722 UK Biobank controls and a validation cohort of 92 SCAD survivors. We performed a research diagnostic screen for pathogenic variants, and exome-wide and gene-set rare variant collapsing analyses.Results - The majority of patients within both cohorts are female, 29% of the study cohort and 14% validation cohort have a remote arteriopathy. Four cases across the two cohorts had a diagnosed connective tissue disorder. We identified pathogenic or likely pathogenic variants in seven genes (PKD1, COL3A1, SMAD3, TGFB2, LOX, MYLK, and YY1AP1) in 14/384 cases in the study cohort and in 1/92 cases in the validation cohort. In our rare variant collapsing analysis, PKD1 was the highest ranked gene and several functionally plausible genes were enriched for rare variants, although no gene achieved study-wide statistical significance. Gene-set enrichment analysis suggested a role for additional genes involved in renal function.Conclusions - By studying the largest sequenced cohort of SCAD survivors we demonstrate that, based on current knowledge, only a small proportion have a pathogenic variant that could explain their disease. Our findings strengthen the overlap between SCAD and renal and connective tissue disorders and we highlight several new genes for future validation.</div
Enrichment for coding variants amongst autosomal SNPs stratified between South Asians and the 1000 Genome populations (3A) and for specific functional classes of SNPs amongst South Asians compared to Europeans (3B).
<p>Enrichment is calculated compared to null hypothesis; P values are provided in <b>Table S6 and Table S7 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102645#pone.0102645.s021" target="_blank">File S1</a></b>.</p
Enrichment for stratified genetic variants at genetic loci associated with respective phenotype in genome-wide association studies.
<p>Inset the correlation between the enrichment for stratified SNPs at known genetic loci, and enrichment of stratified variants for SNPs associated with respective phenotype in genome-wide association studies. Further details are provided in <b>Table S10 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102645#pone.0102645.s021" target="_blank">File S1</a></b>.</p
Correlation between imputed and observed genotypes amongst South Asians, using phased or unphased genotypes from low coverage WGS, or using 1000 Genomes Project data.
<p>Results are shown as mean r<sup>2</sup> with genotypes observed from microarray data (<b>2A</b>) or high-coverage WGS (<b>2B</b>, WGS-28x).</p
Location of birth (1A) and principal components analysis (PCA, 1B) of the South Asians sequenced.
<p>The PCA plots shows results for all South Asians in the LOLIPOP study (SA - All, red circles), for South Asians sequenced (SA - NGS, black dots) and for HapMap2 populations.</p