One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Sodium is an essential mineral and nutrient used in dietary practices across the world and is important to maintain proper blood volume and blood pressure. A high sodium diet is associated with increased expression of β—myosin heavy chain, decreased expression of α/β—myosin heavy chain, increased myocyte enhancer factor 2/nuclear factor of activated T cell transcriptional activity, and increased salt-inducible kinase 1 expression, which leads to alteration in myocardial mechanical performance. A high sodium diet is also associated with alterations in various proteins responsible for calcium homeostasis and myocardial contractility. Excessive sodium intake is associated with the development of a variety of comorbidities including hypertension, chronic kidney disease, stroke, and cardiovascular diseases. While the American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines recommend limiting sodium intake to both prevent and manage heart failure, the evidence behind such recommendations is unclear. Our review article highlights evidence and underlying mechanisms favoring and contradicting limiting sodium intake in heart failure.

Selenium (Se) is a trace nutrient that promotes human health through its incorporation into selenoproteins in the form of the redox-active amino acid selenocysteine (Sec). There are 25 selenoproteins in humans, and many of them play essential roles in the protection against oxidative stress. Selenoproteins, such as glutathione peroxidase and thioredoxin reductase, play an important role in the reduction of hydrogen and lipid hydroperoxides, and regulate the redox status of Cys in proteins. Emerging evidence suggests a role for endoplasmic reticulum selenoproteins, such as selenoproteins K, S, and T, in mediating redox homeostasis, protein modifications, and endoplasmic reticulum stress. Selenoprotein P, which functions as a carrier of Se to tissues, also participates in regulating cellular reactive oxygen species. Cellular reactive oxygen species are essential for regulating cell growth and proliferation, protein folding, and normal mitochondrial function, but their excess causes cell damage and mitochondrial dysfunction, and promotes inflammatory responses. Experimental evidence indicates a role for individual selenoproteins in cardiovascular diseases, primarily by modulating the damaging effects of reactive oxygen species. This review examines the roles that selenoproteins play in regulating vascular and cardiac function in health and disease, highlighting their antioxidant and redox actions in these processes.

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unknown. We utilize a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced and with preserved ejection fractions based on current clinical definitions, to conduct detailed genetic analyses of the two heart failure sub-types. We find different genetic architectures and distinct genetic association profiles between heart failure with reduced and with preserved ejection fraction suggesting differences in underlying pathobiology. The modest genetic discovery for heart failure with preserved ejection fraction (one locus) compared to heart failure with reduced ejection fraction (13 loci) despite comparable sample sizes indicates that clinically defined heart failure with preserved ejection fraction likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of heart failure with preserved ejection fraction is paramount to better dissect the underlying genetic signals and contributors to this highly prevalent condition.