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Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

While dietary intake is linked to stroke risk, surrogate markers that could inform personalized dietary interventions are lacking. We identified metabolites associated with diet patterns and incident stroke in a nested cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.Levels of 162 metabolites were measured in baseline plasma from stroke cases (n = 1,198) and random controls (n = 904). We examined associations between metabolites and a plant-based diet pattern previously linked to reduced stroke risk in REGARDS. Secondary analyses included 3 additional stroke-associated diet patterns: a Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Southern diet. Metabolites were tested using Cox proportional hazards models with incident stroke as the outcome. Replication was performed in the Jackson Heart Study (JHS). Inverse odds ratio-weighted mediation was used to determine whether metabolites mediated the association between a plant-based diet and stroke risk.Metabolites associated with a plant-based diet included the gut metabolite indole-3-propionic acid (β = 0.23, 95% confidence interval [CI] [0.14, 0.33], p = 1.14 × 10A subset of diet-related metabolites are associated with risk of stroke. These metabolites could serve as surrogate markers that inform dietary interventions. ANN NEUROL 2022.

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis (MESA) which included several hundred individuals with whole genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, ten years apart. We evaluated each multi-omic phenotype’s ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62x and rare frameshift variants 216x as frequently as controls, compared to 13x to 27x for expression or protein effects alone. We developed a Bayesian hierarchical model to prioritize specific rare variants underlying multi-omic signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer’s disease.

For Alzheimer’s disease–a leading cause of dementia and global morbidity–improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer’s disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer’s disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer’s disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer’s disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer’s disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution.

Introduction Obstructive sleep apnea (OSA) is a common disorder characterized by recurrent episodes of upper airway obstruction during sleep resulting in oxygen desaturation and sleep fragmentation, and associated with increased risk of adverse health outcomes. Metabolites are being increasingly used for biomarker discovery and evaluation of disease processes and progression. We aimed to develop a metabolomic risk score (MRS) for OSA and identify individual metabolites associated with OSA to provide insights into the pathogenesis of OSA. Methods We studied 219 metabolites and their associations the apnea hypopnea index (AHI) and with OSA, defined as AHI , in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n=3507) using two methods: (1) association analysis of individual metabolites, and (2) least absolute shrinkage and selection operator (LASSO) regression to identify a subset of metabolites that are jointly associated with OSA, and develop an MRS. We then validated the results in Multi-Ethnic Study of Atherosclerosis (MESA) (n=475), an independent dataset. Results HCHS/SOL participants were 41.72 years old on average, 50.7% female, and 10.2% had OSA. MESA individuals were 68.45 years old on average, 56.2% females, and 46.7% had OSA. When assessing the associations between OSA/AHI and individual metabolites, we identified seven metabolites significantly and positively associated with OSA in HCHS/SOL (FDR p Conclusion We developed an MRS that replicated in an independent multi-ethnic dataset, demonstrating the robustness of metabolomic-based OSA risk score to population heterogeneity. Replicated metabolite associations may provide insights into OSA-related molecular and metabolic mechanisms. Support (If Any) Support for metabolomics data was graciously provided by the JLH Foundation (Houston, Texas). The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Center on Minority Health and Health Disparities, the National Institute of Deafness and Other Communications Disorders, the National Institute of Dental and Craniofacial Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the Office of Dietary Supplements. The authors thank the staff and participants of HCHS/SOL for their important contributions. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. MESA Family is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, R01HL071259, and by the National Center for Research Resources, Grant UL1RR033176. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). ). Metabolomics for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416) was performed at Broad Institute and Beth Israel Metabolomics Platform (HHSN268201600038I). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This study was supported by NHLBI grant R35HL135818.

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and cardiovascular risk in type 2 diabetes, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. Utilizing an integrated transcriptomic-metabolomics approach, we demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5′ AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Given that these phenotypes mirror the effects of FGF21 to promote lipid oxidation, ketogenesis, and reduction in adiposity, we hypothesized that FGF21 is required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for SGLT2i-mediated induction of lipid oxidation and ketogenesis but is required for reduction in fat mass and activation of lipolysis. Taken together, these data demonstrate that SGLT2 inhibition triggers a fasting-like transcriptional and metabolic paradigm but requires FGF21 for reduction in adiposity.

Given the impact of SGLT2 inhibitors to reduce overall mortality and CV risk in T2D, improved understanding of cellular and transcriptional mechanisms responsible for metabolic effects is required. We fed C57BL/6J mice a 60% high fat diet (HFD) for 4 weeks prior to assignment to one of 3 groups: (1) 60% HFD, (2) HFD with canagliflozin (CANA, 25 mg/kg/day), and (3) HFD weight-matched (WM) to CANA via caloric restriction. Mice were analyzed after 4-8 weeks. CANA reduced fasting glucose by 47% (P To identify potential mechanisms responsible for these fasting-like phenotypes, we analyzed the molecular impact of CANA. Liver transcriptomic analysis revealed marked downregulation of lipogenesis, glycolysis, and steroid synthesis pathways (p Disclosure S. Osataphan: None. C. Macchi: None. V. Sales: None. C. Kozuka: None. J.I. Chimene-Weiss: None. Y. Tangjaroenpaisan: None. J. Morningstar: None. R. Gerszten: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.

Background: We recently applied a liquid chromatography tandem mass spectrometry (LC-MS/MS) based proteomics platform to plasma samples from individuals undergoing a “planned” myocardial infarction (PMI; alcohol ablation for hypertrophic cardiomyopathy) and identified acyl-CoA binding protein (ACBP) as a potential circulating biomarker of myocardial injury. ACBP is a 10 kDa intracellular protein that is highly expressed in cells with a high turn-over of fatty acids such as cardiomyocytes. We sought to determine the site of ACBP release and whether ischemia alone is sufficient to trigger an increment in plasma levels in humans. Methods: Coronary sinus (CS) and peripheral venous samples were obtained simultaneously from PMI patients; peripheral venous samples were obtained from derivation/validation cohorts of subjects undergoing cardiac stress testing. Plasma ACBP levels were measured by immunoassay. Results: In PMI patients (n=11), pre-injury levels of ACBP were comparable in the CS and peripheral samples. As early as 10 min after PMI, ACBP levels were 27% higher in the CS than in the periphery (P = 0.01), and remained 30% higher at 60 minutes (P = 0.02). Next, we studied 105 patients undergoing cardiac stress testing, 52 of whom demonstrated inducible ischemia (cases) and 53 of whom did not (controls). Baseline ACBP levels were comparable in cases and controls. Changes in median ACBP levels after the exercise stress challenge were significantly greater in the ischemic patients (cases) than in the controls (22% increase in cases; 1% decrease in controls; P = 0.0001), findings which were validated in a second cohort of 101 patients subjects (P = 0.002). These findings remained significant in a multivariable model adjusting for age, male sex, diabetes, BMI, smoking, creatinine, hypercholesterolemia, and total minutes of exercise. By contrast, the effects of exercise on established biomarkers (cTnI, NT-proBNP and FABP) did not differ betwen cases and controls. Conclusions: We provide initial verification that ACBP is rapidly released from the injured heart and increases in response not only to infarction but also ischemia. These findings motivate additional clinical studies of this novel biomarker in heterogeneous patient cohorts.