Exploring Coronary Artery Disease GWAs Targets With Functional Links to Immunometabolism

Abstract

Finding genetic variants that cause functional disruption or regulatory change among the many implicated GWAs variants remains a key challenge to translating the findings from GWAs to therapeutic treatments. Defining the causal mechanisms behind the variants require functional screening experiments that can be complex and costly. Prioritizing variants for functional characterization using techniques that capture important functional and regulatory elements can assist this. The genetic architecture of complex traits such as cardiovascular disease and type II diabetes comprise an enormously large number of variants of small effect contributing to heritability and spread throughout the genome. This makes it difficult to distinguish which variants or core genes are most relevant for prioritization and how they contribute to the regulatory networks that become dysregulated leading to disease. Despite these challenges, recent GWAs for CAD prioritized genes associated with lipid metabolism, coagulation and adhesion along with novel signals related to innate immunity, adipose tissue and, vascular function as important core drivers of risk. We focus on three examples of novel signals associated with CAD which affect risk through missense or UTR mutations indicating their potential for therapeutic modification. These variants play roles in adipose tissue function vascular function and innate immunity which form the cornerstones of immuno-metabolism. In addition we have explored the putative, but potentially important interactions between the environment, specifically food and nutrition, with respect to key processes.

Cardiovascular Disease and Hair Cortisol: a Novel Biomarker of Chronic Stress

“…Certain individuals might be more susceptible to stress-induced CVD owing to their genetic make-up [29, 32]. Genome-wide association studies (GWAS) have documented associations between numerous single nucleotide polymorphisms (SNPs) and CVD [108] and have helped identify genetic variants in biomarkers that play a causal role in aetiology [109]. However, the largest GWAS meta-analysis of plasma cortisol to date has only identified three SNPs that were significantly associated with cortisol concentrations [110].…”

KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction

“…Indeed, whereas KRIT1 has been clearly associated with cellular redox homeostasis, variations in hemodynamic forces, including high laminar shear stress and turbulent oscillatory shear stress occurring in the descending thoracic aorta and the aortic arch, respectively, have clearly shown to induce opposite pro-oxidant and antioxidant effects [4]. Consistent with a potential role for KRIT1 in genetic susceptibility to atherosclerosis, two recent genome-wide association studies (GWAS) have implicated another CCM gene, CCM2, in coronary artery disease (CAD), a condition that is usually caused by atherosclerosis [31,82]. Moreover, whereas there is indeed evidence of genetic predisposition to develop atherosclerosis [83], the association between local increase in oxidative stress and regional susceptibility of the aorta to atherosclerosis has been clearly recognized [52], suggesting that KRIT1 deficiency may contribute to this causal relationship.…”

Genome-wide characterization of circulating metabolic biomarkers reveals substantial pleiotropy and novel disease pathways

“…Interestingly, the metabolic effects on the lipoprotein and lipid traits of the lead TRIM5 variant (rs11601507, p.Val112Ile) appear similar to those of the HMGCR variant rs12916 (Figures 2B and 2C), the metabolic effects of which are concordant with those of statin therapy [34][35][36] . The mechanism by which TRIM5 affects lipid and lipoprotein levels and predisposes to coronary artery disease is unclear and it has been speculated to be related to innate immunity 37 . However, our data suggest that TRIM5 may be affecting the hepatic cholesterol synthesis pathway, raising the possibility that inhibition of TRIM5 could provide an alternative therapeutic pathway for reducing the risk of cardiovascular disease via lowering the concentrations of circulating atherosclerotic apoB-containing lipoprotein particles.…”