The polygenic architecture of left ventricular mass mirrors the clinical epidemiology

Abstract

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases. Left ventricular (LV) mass captures the cardiac response to the cumulative exposure of a diverse set of risk factors, and is strongly predictive of future cardiac events and all-cause mortality 1-3. Determining the genetic factors associated with LV mass could identify important predisposing mechanisms that contribute to heart disease. Three genome-wide association studies (GWAS) have only identified a single nucleotide polymorphism (SNP) associated with LV mass 4-6. Thus, the genetic architecture underlying LV mass remains uncharacterized.

Genetic Determinants of Body Mass Index and Fasting Glucose Are Mediators of Grade 1 Diastolic Dysfunction

“…A GWAS did not identify common SNPs significantly associated with G1DD status, consistent with prior studies examining diastolic function phenotypes. 16 , 17 However, several of the top SNPs had appeared to have relevance to cardiometabolic phenotypes and the left ventricle. Thus, we examined associations with genetic predictors of established risk factors, which is a more powered approach to detect weak associations.…”

“… 16 However, structural traits related to diastolic function, such as left ventricular mass and other functional left ventricular measures, have been demonstrated to have a significant heritable component based on common SNPs. 17 , 18 This could suggest that diastolic dysfunction is a genetically heterogeneous phenotype representing the accumulated contributions from many risk mechanisms.…”

Association between the APOE gene polymorphism and lipid profile and the risk of atrial fibrillation

“…With the progress in genome-wide association (GWAS) analysis in recent years, genomics has made considerable progress in the prediction of complex human diseases, such as CAD and AF [32]. To date, over 50 pathogenic gene mutations have been revealed to cause AF, which mainly involve cellular signal molecules [33], myocardial structural proteins [34], ion [35] and gap junction channels [36]. Hsu et al [34] reported that subjects with AF carrying the ALDH2*2 polymorphism showed more severe oxidative stress in their atria compared with non-carriers and suggested that ALDH2 may protect from AF-related OR in adjusted model was adjusted for LAD, LVDd, LVSd, LVEF, ALT, AST, UN, Scr, UA, CAD, HF, use of ACEIs, BBs, MRAs, digoxin and diuretics OR: odds ratio; CI: confidence interval.…”

Clinical and Genetic Associations of Deep Learning-Derived Cardiac Magnetic Resonance-Based Left Ventricular Mass

“…Genome-wide association studies (GWAS) of echocardiography-based LVM identified a single susceptibility locus downstream of SPCS3 . 7–9 More recently, a genome-wide association study within 19,000 individuals 10 identified significant variants in the gene TTN associated with CMR-based LVM.…”