Genetic determinants of left ventricular diastolic function
S Rand, J S Bundgaard, A M Small, C Zheng, A Teumer, R S Vasan, EchoGen Consortium, J E Moeller, M Dorr, J J Linde, P Natarajan, J Ghouse, H BundgaardAbstract
Background
Left ventricular (LV) diastolic function relies on active myocardial relaxation and passive cardiac chamber stiffness which is frequently assessed by echocardiography. Abnormal LV diastolic function portends worse outcomes in heart failure (HF), cardiomyopathies, coronary artery disease, and atrial fibrillation. Few studies have evaluated genetic determinants of LV diastolic function.
Methods
We meta-analyzed genome-wide association studies (GWAS) for seven quantitative LV diastolic traits measured by echocardiography using data from the Copenhagen Hospital Biobank and previously published GWAS from the EchoGen consortium. The final meta-analysis will include additional six biobanks to collectively form the ImaGENE consortium. Analyzed traits included transmitral flow velocities (E- and A-wave, E/A ratio), E-wave deceleration time, tissue Doppler parameters (average e’, E/e’), left atrial (LA) diameter. We investigated if lead variants were reported in published GWAS for cardiometabolic traits. We next evaluated genetic correlations (rg) between diastolic traits and published GWAS for cardiomyopathies, heart failure subtypes, and MRI-derived diastolic function traits from the UK Biobank. Results yet to be generated will investigate the clinical application for polygenic risk scores’ ability to predict heart failure subtypes in both UK Biobank and the Million Veteran Program.
Results
Sample sizes for the final ImaGENE meta-analysis will include up to 150,000 individuals. For this analysis, we included up to 72,000 individuals and identified 37 genome-wide significant independent loci associated with five of seven meta-analyzed traits (Fig.1). Several loci overlapped with cardiometabolic risk loci, most prominently hypertensive traits. Others were implicated in cardiomyopathies (MYH7, BAG3, SYNPO2L, PITX2, FHOD3, STRN, SYNPO2L, CDKN1A; Fig.2), but we also found loci near calcium-handling genes (PLN, CASQ2) and natriuretic peptide signalling genes (ANNP, NPR3). Several LV diastolic traits had strong genetic correlation to cMRI-derived traits (rg range from 0.60 [between E/A-ratio and LV strain] to 0.98 [between average e’ and LA passive emptying fraction]; all P < 1.5×10-5). LA diameter, E- and A-wave had moderate genetic correlation with cardiomyopathies, including HFpEF (rg range 0.31 – 0.54; all P < 0.01).
Conclusion
Genetic variation plays a role in several components of diastolic function and are partly underpinned by relevant biology in sarcomere, calcium-handling, and natriuretic signalling genes. Genetic correlation demonstrated that increased early and late diastolic filling as well as increased left atrial diameter positively correlated to HFpEF. Our results will extend beyond the highlights above but currently indicate the variety of biological pathways contributing to cardiac diastolic function.Fig1Fig2