GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Carotid intima-media thickness in UK Biobank: Identification of novel genome-wide loci, sex-specific effects and genetic correlations with obesity and glucometabolic traits

“…In the previously reported loci, on Chr5 there is only one SNP, rs758080886, which reaches GWAS-significant evidence for association with IMTmean which is located 3417b from the previously reported lead SNP rs224904 6 . rs758080886 is not available in the reference panel used by LocusZoom 15 and is therefore not plotted, hence this region is represented by the previously reported SNP, rs224904.…”

“…The single largest study within the metaanalysis included 8,663 individuals (approximately evenly split between men and women. That meta-analysis reported 11 robustly associated loci 6 , of which nine lead SNPs were available in UKB (Stable 2). Seven of these demonstrated significant (p<0.05) associations with IMTmean, with consistent effect directions when compared to the previous report 6 (Stable 2).…”

“…Genetic analyses of clinical cohorts have begun to identify single nucleotide polymorphisms (SNPs) associated with increased cIMT [4][5][6][7] , which paves the way for better understanding of processes leading to cardiovascular events. A limitation for these studies (N~68,000) has been heterogeneity in recruitment and ultrasound methodology, which could lead to failure to detect some true genetic effects.…”

Carotid intima‐media thickness predicts carotid plaque development: Meta‐analysis of seven studies involving 9341 participants

“…On the one hand, cIMT and carotid plaque may represent distinct phenotypes of vascular remodelling . This theory is underpinned by genetic studies that revealed distinct genes to be associated with cIMT and carotid plaque . On the other hand, cIMT and carotid plaque are considered to represent different stages of atherogenesis characterised by continuous arterial wall growth.…”

“…15,16 This theory is underpinned by genetic studies that revealed distinct genes to be associated with cIMT and carotid plaque. 17,18 On the other hand, cIMT and carotid plaque are considered to represent different stages of atherogenesis characterised by continuous arterial wall growth. Following this theory would imply cIMT being a predictive measure for the initiation and development of new carotid plaque and would further endorse the relevance of cIMT as a tool to quantify atherosclerosis-and identify individuals at elevated risk for future CVD-at a very early stage.…”