Genetic variation in the endothelin eta receptor contributes to microvascular angina

Abstract Introduction Identifying heritable risk in coronary artery disease is key to delivering ‘precision medicine’. Thus far over 200 relevant genetic loci are described, however only a minority have proven biological effects 1. Examples include a single nucleotide polymorphism (SNP) linked to the endothelin (ET-1) vasoconstrictor pathway. Dysregulation of ET-1 is important in microvascular angina, however it is unknown if other genetic variants contribute 2. Purpose We aimed to identify genetic endotypes of microvascular angina likely to benefit from ET-1 receptor antagonist drugs. Methods 93 participants with microvascular angina were recruited prospectively from 10 hospitals in the United Kingdom to an observational sub-study of the Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial 3. Phenotypic variables including exercise test parameters, health status questionnaires, quantitative perfusion cardiac MRI, and plasma biomarkers, were measured. Cardiac MRI scans were performed according to standard protocol at 1.5T and 3.0T field strength. Perfusion images were acquired during adenosine induced hyperaemia. A myocardial perfusion index (MPI) was calculated using the maximal upslope of signal-intensity-time profiles for each myocardial segment, sub-divided into layers. The ratio of the MPI in the subendocardium and the subepicardium was calculated to give the stress endocardial:epicardial ratio. DNA was genotyped using the UK Biobank Axiom array. Plasma ET-1 peptides were quantified using immunosorbent immunoassay. Analysis was focused on six ET-1 related SNPs (rs5370, rs5443, rs9349473, rs6842241, rs17366743, rs2731672): chosen for high phenome-wide associations for cardiovascular disease, and with nearby prioritised genes. Results Amongst 88 genotyped patients, those possessing the risk A allele of the EDNRA (Endothelin Receptor Type A) related SNP: rs6842241 had significantly higher ET-1 levels than those with the homozygous C genotype (2.01 1.40, 2.38 pg/ml vs 1.43 1.14, 1.94 pg/ml). Stress sub-endocardial hypoperfusion on cardiac MRI was more likely in patients with the A allele, occurring in 4/5, versus 5/17 with the homozygous C genotype, X2=4.09, p=0.04. Patients with the A allele had higher resting diastolic blood pressure (82 74, 90 mmHg vs 75 70, 82 mmHg, p=0.04). No significant differences were detected in clinical variables between the other genotyped SNPs. Conclusions In a microvascular angina population, an EDNRA gene SNP, rs6842241, is associated with adverse clinical features, likely related to excess circulating ET-1.PRIZE ET Sub-study flow-chart Plasma ET-1 levels by genotype