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GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease.

ABSTRACT: Coronary artery disease (CAD) is the leading cause of mortality worldwide and poses a considerable public health burden. Recent genome-wide association studies (GWAS) have revealed >100 genetic loci associated with CAD susceptibility in humans. While a number of these loci harbor gene targets of currently approved therapies, such as statins and PCSK9 inhibitors, the majority of the annotated genes at these loci encode for proteins involved in vessel wall function with no known drugs available. Importantly many of the associated genes linked to vascular (smooth muscle, endothelial, and macrophage) cell processes are now organized into distinct functional pathways, e.g., vasodilation, growth factor responses, extracellular matrix and plaque remodeling, and inflammation. In this mini-review, we highlight the most recently identified loci that have predicted roles in the vessel wall and provide genetic context for pre-existing therapies as well as new drug targets informed from GWAS. With the development of new modalities to target these pathways, (e.g., antisense oligonucleotides, CRISPR/Cas9, and RNA interference) as well as the computational frameworks to prioritize or reposition therapeutics, there is great opportunity to close the gap from initial genetic discovery to clinical translation for many patients affected by this common disease.

SUBMITTER: Turner AW

PROVIDER: S-EPMC6026658 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease.

Turner Adam W AW Wong Doris D Dreisbach Caitlin N CN Miller Clint L CL

Frontiers in cardiovascular medicine 20180625

Coronary artery disease (CAD) is the leading cause of mortality worldwide and poses a considerable public health burden. Recent genome-wide association studies (GWAS) have revealed >100 genetic loci associated with CAD susceptibility in humans. While a number of these loci harbor gene targets of currently approved therapies, such as statins and PCSK9 inhibitors, the majority of the annotated genes at these loci encode for proteins involved in vessel wall function with no known drugs available. I ...[more]

PMID: 29988570

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Project description:BackgroundData of susceptible gene polymorphisms related to progression of coronary atherosclerosis in patients with three-vessel disease (TVD) is limited in China. This case-control study aimed to analyze the differences of variant carrier frequencies between cases and controls, and to explain the possible genetic effects on the progression of TVD.MethodsA total of 8943 TVD patients were consecutively enrolled. Major adverse cardiac and cerebrovascular events (MACCE) included all-cause death, acute myocardial infarction, repeat revascularization, readmission and stroke. Patients with 1-year MACCE in this cohort were selected as MACCE group. Blood samples from MACCE group and non-CAD control groups were collected, and a deoxyribonucleic acid library was created. A total of 34 tag or hot single nucleotide polymorphisms (SNPs) in six genes including CDKN2B-AS1, ADAMTS7, ABO, ADAMTS13, IL-18, and PECAM1 were analyzed by a SNPscan™ multi-genotyping kit. Carrier frequencies of each SNP were compared between the two groups using dominant, recessive and codominant allele model, respectively. Multivariate logistic regression model was established.ResultsVariant allele frequencies of rs10757274, rs1333042, rs1333049, rs4977574, rs9632884, rs1063192 and rs3217986 on CDKN2B-AS1 gene showed significant differences between the two groups in at least one allele model. Variant allele frequency of rs3217986 was not statistically significant after adjusting for the false discovery rate using Benjamini-Hochberg procedure (Q > 0.05). Variant allele frequencies of rs1333049, rs10757274, rs4977574 on CDKN2B-AS1 gene were significantly higher in MACCE group in all dominant, recessive and codominant models. Rs1055432 on ADAMTS13 and rs8176694 on ABO gene showed threshold significance between the two groups. After multivariable adjustment, G mutant homozygous rs9632884 (GG vs. GC + CC) (OR: 0.24; 95% CI: 0.09-0.65; P = 0.005) on CDKN2B-AS1 gene were independent protective factor of MACCE in recessive model.ConclusionsIn patients with TVD in China, variant alleles on CDKN2B-AS1 gene may form part of the genetic basis of coronary atherosclerosis progression, promoting or suppressing ischemic events.

Project description:ObjectivesComputed tomography (CT)-derived fractional flow reserve (FFRCT) decreases continuously from proximal to distal segments of the vessel due to the influence of various factors even in non-obstructive coronary artery disease (NOCAD). It is known that FFRCT is dependent on vessel-length, but the relationship with other vessel morphologies remains to be explained.PurposeTo investigate morphological aspects of the vessels that influence FFRCT in NOCAD in the right coronary artery (RCA).MethodsA total of 443 patients who underwent both FFRCT and invasive coronary angiography, with < 50% RCA stenosis, were evaluated. Enrolled RCA vessels were classified into two groups according to distal FFRCT: FFRCT ≤ 0.80 (n = 60) and FFRCT > 0.80 (n = 383). Vessel morphology (vessel length, lumen diameter, lumen volume, and plaque volume) and left-ventricular mass were assessed. The ratio of lumen volume and vessel length was defined as V/L ratio.ResultsWhereas vessel-length was almost the same between FFRCT ≤ 0.80 and > 0.80, lumen volume and V/L ratio were significantly lower in FFRCT ≤ 0.80. Distal FFRCT correlated with plaque-related parameters (low-attenuation plaque, intermediate-attenuation plaque, and calcified plaque) and vessel-related parameters (proximal and distal vessel diameter, vessel length, lumen volume, and V/L ratio). Among all vessel-related parameters, V/L ratio showed the highest correlation with distal FFRCT (r = 0.61, p < 0.0001). Multivariable analysis showed that calcified plaque volume was the strongest predictor of distal FFRCT, followed by V/L ratio (β-coefficient = 0.48, p = 0.03). V/L ratio was the strongest predictor of a distal FFRCT ≤ 0.80 (cut-off 8.1 mm3/mm, AUC 0.88, sensitivity 90.0%, specificity 76.7%, 95% CI 0.84-0.93, p < 0.0001).ConclusionsOur study suggests that V/L ratio can be a measure to predict subclinical coronary perfusion disturbance.Clinical relevance statementA novel marker of the ratio of lumen volume to vessel length (V/L ratio) is the strongest predictor of a distal CT-derived fractional flow reserve (FFRCT) and may have the potential to improve the diagnostic accuracy of FFRCT.Key points• Physiological FFRCT decline depends not only on vessel length but also on the lumen volume in non-obstructive coronary artery disease in the right coronary artery. • FFRCT correlates with plaque-related parameters (low-attenuation plaque, intermediate-attenuation plaque, and calcified plaque) and vessel-related parameters (proximal and distal vessel diameter, vessel length, lumen volume, and V/L ratio). • Of vessel-related parameters, V/L ratio is the strongest predictor of a distal FFRCT and an optimal cut-off value of 8.1 mm3/mm.

Dataset Information

GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease.

Publications

GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease.

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