The growing role of genomics and genetics in the management of cardiovascular diseases

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on genetics starts with a Viewpoint article entitled ‘Education in cardiovascular genomics and genetics: time for action’ by Giuseppe Limongelli from The University of Campania Luigi Vanvitelli in Naples, Italy, and colleagues which address the important topic of education in cardiogenetics and cardiogenomics, an emerging field in cardiology, with progressive and targeted education needs for students, scientists, clinicians, and different healthcare professional figures.1 In December 2024, the European Society of Cardiology (ESC) Council for Cardiogenomics met to discuss the current state of the art in cardiovascular genetic medicine enriched by several recent excellent publications.2–11 The group sought to address a key question in contemporary cardiology: namely, is it time to include education in cardiovascular genetics and genomics in the core training for cardiologists? The answer was an unequivocal yes, given its potential to improve the diagnosis and treatment of cardiovascular disease. However, the challenge lay in determining the most effective means of achieving this goal. Certain genetic forms of dilated cardiomyopathy (DCM) entail a higher arrhythmic risk. It is unknown whether DCM patients with high-risk arrhythmic genotypes also develop more advanced heart failure (AHF) complications. In a Fast Track Congress article entitled ‘Arrhythmic genotypes in dilated cardiomyopathy and risk of advanced heart failure’, Nerea Mora-Ayestarán from Puerta de Hierro Majadahonda University Hospital in Madrid, Spain, and colleagues report their study of AHF events in a large multicentre cohort of genotyped patients with DCM receiving contemporary treatment, with a special focus on individuals with variants in high-risk arrhythmic genes.12 Clinical data from 1203 genotyped DCM patients were collected from 19 Spanish centres. Patients were classified into high-risk arrhythmic genotypes (LMNA, FLNC, desmosomal genes, PLN, TMEM43, and RBM20), TTN, other genes, and genotype negative (Gen−). The primary endpoint was a composite of AHF events (ventricular assist device implantation, heart transplant, and AHF-related mortality). The secondary endpoint was a combination of malignant ventricular arrhythmias (MVAs). A DCM-causing variant was identified in a high-risk arrhythmic gene in 16% of patients, 16% had variants in TTN, 11% in other genes, and 57% were Gen−. After a median follow-up of 5.7 years, AHF events occurred in 24.3% of patients in the high-risk arrhythmic group, and in 18.7, 13, and 10.1% of patients with other genotypes, TTN, and Gen−, respectively (hazard ratio 1.85 for high-risk arrhythmic genes compared with other groups). MVA occurred in 29.7% of patients (hazard ratio 2.52 for high-risk genotypes vs other groups). High-risk arrhythmic genotype was the main independent predictor of AHF in multivariate analysis. High-risk arhythmic genotype and late gadolinium enhancement were independent predictors of MVA (Figure 1). 12 The authors conclude that patients with high-risk arrhythmic genotypes also experience more AHF events, supporting a differential therapeutic approach in this group of patients beyond sudden death prevention. The manuscript is accompanied by an Editorial by Jean-Benoît le Polain de Waroux and Maarten De Smet from the St-Jan’s Hospital in Bruges, Belgium.13 The authors underscore that the study of Mora-Ayestarán and co-authors was a Spanish national effort with a, presumably, largely Caucasian population. The question remains of whether these results may be generalized to populations with other genetic backgrounds. This is especially relevant in patients with DCM. As mentioned previously, rare monogenic variants are easy to determine, but for most patients the risk of developing life-threatening arrhythmias or HF is also determined by other genetic and environmental factors. Nevertheless, this research opens the door for the development and implementation of risk scores that, in addition to arrhythmic risk, assess the probability of progression to AHF and provide guidance on when to start specific treatment. In this regard, future studies exploring the impact of intermediate effect and common variants on the DCM phenotype and the development of polygenic risk scores to predict arrhythmic and HF outcomes and treatment efficacy are warranted. Acquired somatic mutations are a hallmark of ageing and are increasingly recognized as contributors to disease susceptibility. Mosaic loss of the Y chromosome (mLOY) in leucocytes represents the most common form of acquired clonal mosaicism in men, and is associated with incident cardiovascular diseases including HF, atrial fibrillation, fatal myocardial infarction in men with coronary artery disease (CAD), or HF-associated death in chronic kidney disease.14,15 While the genetic predisposition to mLOY has been recently investigated, the effects of mLOY on the systemic proteome signature have not been comprehensively characterized. In a Fast Track Congress article entitled ‘Loss of Y chromosome: proteomic signatures in human cardiovascular disease’, Michael Weyrich from Goethe University Frankfurt in Germany, and colleagues examine the association between mLOY and the plasma proteome signature in men enrolled in the UK Biobank.16 mLOY cells revealed concordant up-regulation of the coding genes for 47 of the 173 (=27%) proteins significantly associated with incident HF. The up-regulated genes in peripheral blood mononuclear cells demonstrated signature pathway enrichment related to inflammation and the innate and adaptive immune system concordant with the proteomic plasma signature. Specifically, the up-regulated genes in mLOY cells included those genes coding for the proteins PLAUR, CD300E, LILRA5, TNFRSF10B, and LAMP3, which all were significantly associated with the incidence for and mortality from all four cardiovascular disease conditions, HF, atrial fibrillation, hypertensive heart disease, and aortic aneurysm. The authors conclude that mLOY amplifies pathogenic pathways well established to contribute not only to cardiovascular disease incidence but also to cardiovascular mortality, and may thus offer novel therapeutic targets in men with mLOY. Truncating variants in the titin gene (TTNtv) are the most common genetic cause of DCM but also occur as incidental findings in the general population. In a Clinical Research article entitled ‘Titin-related familial dilated cardiomyopathy: factors associated with disease onset’, Renee Johnson from the Victor Chang Cardiac Research Institute in Darlinghurst, Australia, and colleagues investigate factors associated with the clinical manifestation of TTNtv.17 An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, and lifestyle) and DCM. A total of ∼3000 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM (OR 21.21). Disease onset was earlier in males but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR 3.41), with a prior history of atrial fibrillation having two-fold increased odds of DCM (OR 2.05). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR 4.75). Administration of beta-adrenergic receptor- or renin–angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR 0.13). The authors conclude that disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention. The manuscript is accompanied by an Editorial by Sean Jurgens and Roddy Walsh from the University of Amsterdam, The Netherlands, and City St George’s, University of London, UK.18 The authors conclude that titin is an exemplar of the challenges, but also the opportunities, of precision medicine approaches for reducing the burden of cardiovascular disease. It highlights the complexity of risk factors (genetic, clinical, and lifestyle) that can combine to determine the risk of developing cardiomyopathy. As TTNtvs are a major cause of DCM and HF but are also prevalent in the general population, it will be critical to strike an effective balance between clinical intervention and avoiding overdiagnosis. Future studies are required to enhance the identification of the most at-risk TTNtv individuals (including incorporation of additional genetic risk factors) and demonstrate the efficacy of personalized lifestyle and medical intervention to reduce the incidence and severity of this debilitating disease. There is growing interest in familial hypercholesterolaemia (FH).19–22 Cholesterol screening in children, with subsequent genetic testing of the top percentile, has been suggested as an efficient universal screening approach in FH. In a Clinical Research article entitled ‘LDL-cholesterol in newborns and children with genetically verified familial hypercholesterolaemia: implications for cholesterol-based screening’, Martin Prøven Bogsrud from Oslo University Hospital in Norway, and colleagues investigate cholesterol levels measured in umbilical cord blood from newborns and venous blood samples in children from 1 to 12 years old in the Norwegian national family cascade screening programme for families with FH from 1998 to 2023.23 Cholesterol levels (umbilical cord in newborns [n = 113] and venous blood in children 1–12 years old [n = 1346]) in variant-positive and variant-negative children were compared. LDL cholesterol (LDL-C) was higher in FH newborns vs non-FH newborns (1.22 vs 068 mmol/L, P < .001), but overlapped widely. Cut-off levels corresponding to the 95th and 85th percentile would only identify 55.7% and 75.4% of newborns with FH, respectively. Screening efficacy in newborns did not differ in subgroups: boys and girls, null and non-null variants, variant gene, and neither for total cholesterol nor for non-HDL cholesterol. In all other age groups (from 1 to 12 years), LDL-C discriminated highly between mutation FH and non-FH children. Cut-off levels corresponding to the 95th and 85th percentile of LDL-C would identify 88.4% and 94.1% of 1- to 12-year-old children with FH, respectively. The authors conclude that previous studies investigating lipid or genetic screening approaches for FH have limitations of only performing genetic testing in children with high LDL-C levels. The present study is the first to show the true LDL-C overlap in children with FH vs non-FH by utilizing unique data from a national family cascade screening programme. Cholesterol-based screening approaches for FH only seem feasible from 1 year of age onward. The manuscript is accompanied by an Editorial by Sofie Taageby Nielsen and Ruth Frikke-Schmidt from Copenhagen University Hospital Rigshospitalet in Denmark.24 The authors conclude that taken together, LDL-C concentrations measured from 1 to 12 years of age in a cohort participating in a national cascade screening programme with genetic testing clearly demonstrate screening efficiency for FH identification. Because an immediate treatment consequence is available from 6 years of age, this seems like optimal timing for genetic verification of FH in children. Translating human genomic discoveries into mechanistic insights requires linking genetic variations to candidate genes and their causal functional phenotypes. Genome-wide association studies (GWASs) have consistently identified LIPA (lipase A, lysosomal acid type) as a risk locus for CAD, with previous analyses prioritizing LIPA as a likely causal gene. However, functional studies elucidating causal variants, regulatory mechanisms, target cell types, and their causal impact on atherosclerosis have been lacking. In a Translational Science article entitled ‘LIPA, a risk locus for coronary artery disease: decoding the variant-to-function relationship’, Fang Li from Columbia University Irving Medical Center in New York, NY, USA, and colleagues aim to address this gap by establishing the variant-to-function relationship at the LIPA locus.25 Post-GWAS pipelines and molecular biology techniques, including expression quantitative trait loci analysis, Tri-HiC, luciferase assay, CRISPRi, allele-specific binding, motif analysis, and electrophoretic mobility shift assay, were used to link functional variants to target genes and define the direction of their regulatory effects in causal cell types. To determine how increased myeloid LIPA impacts atherosclerosis, myeloid-specific LIPA overexpression mice on an Ldlr−/− background were generated. CAD risk alleles in the LIPA locus increased LIPA expression and enzyme activity specifically in monocytes/macrophages by enhancing PU.1 binding to an intronic enhancer region that interacts with the LIPA promoter. Myeloid-specific LIPA overexpression in Ldlr−/− mice fed a western diet resulted in larger atherosclerotic lesions, accompanied by altered macrophage function, characterized by increased accumulation of lesional macrophages derived from circulating monocytes, reduced neutral lipid content, and up-regulation of integrin and extracellular matrix pathway genes (Figure 2). Overview of the study design and key findings. This study investigates the variant-to-function relationship at the CAD-associated LIPA locus and determines whether LIPA causally contributes to atherosclerosis. Functional genomic studies showed that LIPA-risk alleles increase LIPA expression and enzyme activity in monocytes/macrophages. Complementary mouse models with myeloid-specific LIPA overexpression confirmed a causal role for elevated myeloid LIPA in promoting atherosclerosis by altering macrophage function, characterized by increased lesional macrophage accumulation, reduced neutral lipid content, and up-regulation of integrin and ECM pathway genes. These findings establish a direct causal link between LIPA-risk alleles and atherosclerosis via increased monocyte/macrophage LIPA, translating human genetic associations into mechanistic insights. CAD, coronary artery disease; ECM, extracellular matrix; EMSA, electrophoretic mobility shift assay; eQTL, expression quantitative trait loci; GWAS, genome-wide association study; KI, knock-in; LIPA, lipase A, lysosomal acid type25 The authors conclude that this study establishes a direct causal link between LIPA risk alleles and increased monocyte/macrophage LIPA that exacerbates atherosclerosis, bridging human functional genomic evidence to the mechanistic understanding of CAD. The manuscript is accompanied by an Editorial by Philipp Wild and Tanja Zeller from Johannes Gutenberg University of Mainz and the University of Luebeck in Germany.26 The authors conclude that Li et al. present a model example of post-GWAS research, opening up new avenues for targeted therapies and underscoring the importance of in-depth functional and experimental analyses to fully realize the potential of GWAS discoveries. The authors state that as researchers involved in the initial discovery of LIPA as a CAD-associated locus through GWAS, they find personally fulfilling to see this locus progress from a statistical association to detailed mechanistic insight—offering a model for how GWAS signals can be translated into functional understanding and clinical relevance. Clonal haematopoiesis of indeterminate potential (CHIP) involves age-related acquisition and expansion of genes frequently mutated in haematological malignancies (e.g. DNMT3A, TET2, or JAK2). JAK2 heightens cardiovascular disease risk. In particular, individuals with JAK2 CHIP have a four-fold increased risk of cardiovascular disease. In a Rapid Communications article entitled ‘Interleukin-17 receptor-A signalling: atheroprotective role in JAK2 clonal haematopoiesis’, Kun Zhao from Vanderbilt University Medical Center, Nashville, TN, USA, and colleagues hypothesize that interleukin-17 receptor-A (IL-17RA) signalling modifies cardiovascular disease risk among individuals with JAK2-CHIP.27 In >500 000 people in the UK Biobank and Vanderbilt’s BioVU, genetically predicted IL-17RA levels reduced the risk of cardiovascular disease exclusively in those with JAK2-CHIP. Further, only JAK2-CHIP carriers with low genetically predicted IL-17RA levels were at heightened risk of cardiovascular disease incidence. Mechanistic studies using atheroprone JAK2-V617F mice suggested that inflammasome activation and plasma membrane rupture mediated by Ninjurin-1 may create a protective feedback mechanism where Th17 cells signal to TREM2 macrophages via IL-17RA, thereby dampening inflammatory responses. The authors conclude that JAK2-CHIP patients treated with IL-17 blockade may experience elevated CVD risk. The issue is also complemented by two Discussion Forum contributions. In the commentary entitled ‘The limitations of biomarkers in addressing bias in alcohol and cardiovascular disease research’, Elizabeth Farkouh, Shantanu Srivatsa, and Michael Farkouh from Mayo Clinic Alix School of Medicine in Rochester, MN, USA, UNC Chapel Hill School of Medicine in NC, USA, and Cedars Sinai Health System in Los Angeles, CA, USA comment on the recently published paper entitled ‘Urinary tartaric acid as a biomarker of wine consumption and cardiovascular risk: the PREDIMED trial’, by Inés Domínguez-López et al., from the University of Barcelona, in Spain.28,29 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Lindsay Washington, Johanna Huggler, Amelia Meier-Batschelet, and Martin Meyer for help with compilation of this article.