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Genome-wide association studies provide important new mechanistic insights

With advances in technology, genome-wide association (GWA) studies are increasingly being used to identify genetic variants associated with particular diseases. Described here are three GWA studies presented at ESC Congress 2020 that illustrate the powerful nature of this approach in the investigation of cardiovascular diseases.

Basic Science
Valvular, Myocardial, Pericardial, Pulmonary, Congenital Heart Disease
Diseases of the Aorta, Peripheral Vascular Disease, Stroke

At a Young Investigator Award Session yesterday, Doctor Chayakrit Krittanawong (Baylor College of Medicine, Houston, Texas, USA) described a GWA analysis that identified novel susceptibility loci associated with pulmonary embolism (PE). In total, 5,466 PE cases and 461,219 ancestry-­matched controls were studied from the UK Biobank. Significant associations for PE were identified in 63 independent genetic loci (p<5.0×10−7). Of note, lipid metabolism (LIPC, LCAT, NPC2)- and caffeine metabolism (NAT2)-related genetic loci appeared to play an important role in PE, alongside genes already associated with coagulation-­thrombosis pathways (VWF, THPO, PTPN11, INPP5D, UROS, HMBS) (all p­values <0.05). The authors concluded that this research has uncovered unexpected novel factors for PE pathophysiology, but noted that the results need to be validated in different cohorts and populations.

At a Young Investigator Award Session today, Ms. Hao Yu Chen (McGill University, Montreal, Canada) described a GWA meta-analysis that identified nine novel susceptibility loci for aortic stenosis (AS). In total, 11,591,806 variants were analysed from 652,134 participants (13,758 cases of AS) in 10 European cohorts spanning five countries. Eighteen independent variants at 16 loci attained genome­wide significance (p≤5×10-8), including variants at all seven previously reported loci. A weighted polygenic risk score composed of the 18 variants was strongly associated with AS (adjusted odds ratio [OR] per standard deviation 1.38; 95% confidence interval [CI] 1.33 to 1.44; p=4.6×10­57) and improved the identification of cases when added to a model containing clinical risk factors (p=2.0×10-11).

The meta-analysis also provided evidence that inflammation and lipid metabolism may be key contributors to AS. Gene-­based approaches indicated higher IL6R expression in the blood among AS cases compared with controls (p=3.1×10­6) and showed an association of LDLR with AS (p=2.3×10­10). Genes regulated by transcription factor TCF7 and micro­-RNAs miR-­21, miR­-219, miR­-491 and miR­-19 were also differentially expressed in the liver of AS cases (p≤5.7×10­4), suggesting disease development may be mediated by tissue­-specific transcriptional and post­-transcriptional regulation. Mendelian randomisation supported a causal association of three lipid traits with AS, including low­-density lipoprotein cholesterol (OR per mmol/L 1.61; 95% CI 1.48 to 1.75; p=1.3×10­30).

In an ePoster, Doctor Julien Barc (l'institut du thorax, University of Nantes, France) and international collaborators explored new susceptibility loci associated with Brugada syndrome, a disorder associated with sudden cardiac death. Screening for pathogenic rare variants in SCN5A, encoding for the cardiac sodium channel NaV1.5, uncovers mutations in only ~20% of patients. Dr. Barc et al conducted a GWA study on 2,820 individuals with Brugada syndrome and 10,001 ancestry­-matched controls and identified 21 susceptibility variants (p<5×10­8), of which 18 were novel. Eight were located at the SCN5A­-SCN10A locus, emphasising the central role of NaV1.5. Interestingly, nine loci harbour cardiac transcription factor genes (HEY2, TBX20, GATA4, ZFPM2, WT1, TBX5, IRX3, IRX5), pointing to transcriptional regulation as a key feature of Brugada syndrome pathogenesis. Of note, two other signals occurred in the vicinity of genes encoding microtubule- or myofibre-associated proteins (MAPRE2 and MYO18B), which led the authors to conduct experimental studies that demonstrated a role for MAPRE2 in NaV1.5 function. These findings provide further support for a complex genetic architecture underlying susceptibility to Brugada syndrome and highlight potentially new pathophysiological molecular mechanisms. Furthermore, the polygenic risk score for Brugada syndrome, based on the 21 risk haplotypes, was also associated with conduction slowing and atrial fibrillation, providing novel insights into underlying biological pathways.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.