Publications by authors named "Robert E Gerszten"

192 Publications

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19.

JCI Insight 2021 Sep 10. Epub 2021 Sep 10.

Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, United States of America.

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from COVID-19 patients demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.
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http://dx.doi.org/10.1172/jci.insight.151527DOI Listing
September 2021

The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene.

Sci Rep 2021 Aug 2;11(1):15652. Epub 2021 Aug 2.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, PRB 354B, Nashville, TN, 37232, USA.

Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3 mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q < 0.05) with the SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk.
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http://dx.doi.org/10.1038/s41598-021-95154-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329184PMC
August 2021

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies.

Gut 2021 Jun 14. Epub 2021 Jun 14.

Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.

Objective: Tryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes (T2D), host genetics, diet and gut microbiota.

Method: We analysed associations between circulating levels of 11 tryptophan metabolites and incident T2D in 9180 participants of diverse racial/ethnic backgrounds from five cohorts. We examined host genome-wide variants, dietary intake and gut microbiome associated with these metabolites.

Results: Tryptophan, four kynurenine-pathway metabolites (kynurenine, kynurenate, xanthurenate and quinolinate) and indolelactate were positively associated with T2D risk, while indolepropionate was inversely associated with T2D risk. We identified multiple host genetic variants, dietary factors, gut bacteria and their potential interplay associated with these T2D-relaetd metabolites. Intakes of fibre-rich foods, but not protein/tryptophan-rich foods, were the dietary factors most strongly associated with tryptophan metabolites. The fibre-indolepropionate association was partially explained by indolepropionate-associated gut bacteria, mostly fibre-using . We identified a novel association between a host functional variant (determining lactase persistence) and serum indolepropionate, which might be related to a host gene-diet interaction on gut , a probiotic bacterium significantly associated with indolepropionate independent of other fibre-related bacteria. Higher milk intake was associated with higher levels of gut and serum indolepropionate only among genetically lactase non-persistent individuals.

Conclusion: Higher milk intake among lactase non-persistent individuals, and higher fibre intake were associated with a favourable profile of circulating tryptophan metabolites for T2D, potentially through the host-microbial cross-talk shifting tryptophan metabolism toward gut microbial indolepropionate production.
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http://dx.doi.org/10.1136/gutjnl-2021-324053DOI Listing
June 2021

Human plasma proteomic profiles indicative of cardiorespiratory fitness.

Nat Metab 2021 06 27;3(6):786-797. Epub 2021 May 27.

Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Maximal oxygen uptake (VOmax) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VOmax, and of increases of VOmax in response to exercise training (ΔVOmax), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VOmax and ΔVOmax, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's ΔVOmax. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans.
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http://dx.doi.org/10.1038/s42255-021-00400-zDOI Listing
June 2021

Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions.

PLoS One 2021 27;16(5):e0240764. Epub 2021 May 27.

Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, United States of America.

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with beneficial metabolic changes to weight loss and which distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p = 2.3e-5) and diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in insulin resistance with weight loss. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240764PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158886PMC
May 2021

Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19.

medRxiv 2021 May 17. Epub 2021 May 17.

Profound endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. In the quiescent state, the endothelial surface is anticoagulant, a property maintained at least in part via constitutive signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from activated endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant dysfunction of the endothelium and alterations in the Tie2-angiopoietin axis. Primary human endothelial cells treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. On lung autopsy specimens from COVID-19 patients, we found a prothrombotic endothelial signature as evidenced by increased von Willebrand Factor and loss of anticoagulant proteins. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed profound endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity and highest levels were associated with worse survival. These data highlight the disruption of Tie2-angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Moreover, our findings provide novel rationale for current trials of Tie2 activating therapy with AKB-9778 in severe COVID-19 disease.
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http://dx.doi.org/10.1101/2021.05.13.21257070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142666PMC
May 2021

Associations of circulating choline and its related metabolites with cardiometabolic biomarkers: an international pooled analysis.

Am J Clin Nutr 2021 09;114(3):893-906

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Choline is an essential nutrient; however, the associations of choline and its related metabolites with cardiometabolic risk remain unclear.

Objective: We examined the associations of circulating choline, betaine, carnitine, and dimethylglycine (DMG) with cardiometabolic biomarkers and their potential dietary and nondietary determinants.

Methods: The cross-sectional analyses included 32,853 participants from 17 studies, who were free of cancer, cardiovascular diseases, chronic kidney diseases, and inflammatory bowel disease. In each study, metabolites and biomarkers were log-transformed and standardized by means and SDs, and linear regression coefficients (β) and 95% CIs were estimated with adjustments for potential confounders. Study-specific results were combined by random-effects meta-analyses. A false discovery rate <0.05 was considered significant.

Results: We observed moderate positive associations of circulating choline, carnitine, and DMG with creatinine [β (95% CI): 0.136 (0.084, 0.188), 0.106 (0.045, 0.168), and 0.128 (0.087, 0.169), respectively, for each SD increase in biomarkers on the log scale], carnitine with triglycerides (β = 0.076; 95% CI: 0.042, 0.109), homocysteine (β = 0.064; 95% CI: 0.033, 0.095), and LDL cholesterol (β = 0.055; 95% CI: 0.013, 0.096), DMG with homocysteine (β = 0.068; 95% CI: 0.023, 0.114), insulin (β = 0.068; 95% CI: 0.043, 0.093), and IL-6 (β = 0.060; 95% CI: 0.027, 0.094), but moderate inverse associations of betaine with triglycerides (β = -0.146; 95% CI: -0.188, -0.104), insulin (β = -0.106; 95% CI: -0.130, -0.082), homocysteine (β = -0.097; 95% CI: -0.149, -0.045), and total cholesterol (β = -0.074; 95% CI: -0.102, -0.047). In the whole pooled population, no dietary factor was associated with circulating choline; red meat intake was associated with circulating carnitine [β = 0.092 (0.042, 0.142) for a 1 serving/d increase], whereas plant protein was associated with circulating betaine [β = 0.249 (0.110, 0.388) for a 5% energy increase]. Demographics, lifestyle, and metabolic disease history showed differential associations with these metabolites.

Conclusions: Circulating choline, carnitine, and DMG were associated with unfavorable cardiometabolic risk profiles, whereas circulating betaine was associated with a favorable cardiometabolic risk profile. Future prospective studies are needed to examine the associations of these metabolites with incident cardiovascular events.
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http://dx.doi.org/10.1093/ajcn/nqab152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408854PMC
September 2021

Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults.

Circ Genom Precis Med 2021 Jun 21;14(3):e003191. Epub 2021 May 21.

Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (D.H.K., U.A.T., D.N., M.D.B., X.S., M.J.K., D.S., M.H., J.M.R., Z.-Z.C., D.E.C., B.P., J.G.W., R.E.G.).

Background: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort.

Methods: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women).

Results: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; β=0.04; =2×10; hazard ratio, 1.48; =0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; β=0.05; =5×10). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; =0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups.

Conclusions: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.
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http://dx.doi.org/10.1161/CIRCGEN.120.003191DOI Listing
June 2021

Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions.

Cell Rep Med 2021 May 3;2(5):100287. Epub 2021 May 3.

Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.
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http://dx.doi.org/10.1016/j.xcrm.2021.100287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091031PMC
May 2021

Correlates of Neutralization against SARS-CoV-2 Variants of Concern by Early Pandemic Sera.

J Virol 2021 06 24;95(14):e0040421. Epub 2021 Jun 24.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants.
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http://dx.doi.org/10.1128/JVI.00404-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223959PMC
June 2021

Circulating trimethylamine N-oxide in association with diet and cardiometabolic biomarkers: an international pooled analysis.

Am J Clin Nutr 2021 05;113(5):1145-1156

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities.

Objectives: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia.

Methods: Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant.

Results: After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = -0.047) and blood pressure (β = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses.

Conclusions: In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation.
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http://dx.doi.org/10.1093/ajcn/nqaa430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106754PMC
May 2021

Hepatic Fat in Participants With and Without Incident Diabetes in the Diabetes Prevention Program Outcome Study.

J Clin Endocrinol Metab 2021 03 11. Epub 2021 Mar 11.

J. W. Ruby Memorial Hospital, 1 Medical Center Dr, Morgantown, WV, USA.

Purpose: To characterize hepatic fat content and fatty liver prevalence, their determinants, and effect of interventions to prevent diabetes using computerized tomography in a cohort with prediabetes, in those developing diabetes versus not.

Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units in 1876 participants at ~14 years following randomization into the Diabetes Prevention Program, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed.

Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46±16 vs. 51±14HU; p<0.001) and a greater prevalence of fatty liver (LA<40HU) (34% vs 17%; p<0.001). Severity of metabolic abnormalities at the time of LA evaluation were associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA<40HU prevalence.

Conclusions: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted.
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http://dx.doi.org/10.1210/clinem/dgab160DOI Listing
March 2021

Metabolomic Markers of Southern Dietary Patterns in the Jackson Heart Study.

Mol Nutr Food Res 2021 04 11;65(8):e2000796. Epub 2021 Mar 11.

Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Scope: New biomarkers are needed that are representative of dietary intake.

Methods And Results: We assess metabolites associated with Southern dietary patterns in 1401 Jackson Heart Study participants. Three dietary patterns are empirically derived using principal component analysis: meat and fast food, fish and vegetables, and starchy foods. We randomly select two subsets of the study population: two-third sample for discovery (n = 934) and one-third sample for replication (n = 467). Among the 327 metabolites analyzed, 14 are significantly associated with the meat and fast food dietary pattern, four are significantly associated with the fish and vegetables dietary pattern, and none are associated with the starchy foods dietary pattern in the discovery sample. In the replication sample, nine remain associated with the meat and fast food dietary pattern [indole-3-propanoic acid, C24:0 lysophosphatidylcholine (LPC), N-methyl proline, proline betaine, C34:2 phosphatidylethanolamine (PE) plasmalogen, C36:5 PE plasmalogen, C38:5 PE plasmalogen, cotinine, hydroxyproline] and three remain associated with the fish and vegetables dietary pattern [1,7-dimethyluric acid, C22:6 lysophosphatidylethanolamine, docosahexaenoic acid (DHA)].

Conclusion: Twelve metabolites are discovered and replicated in association with dietary patterns detected in a Southern U.S. African-American population, which could be useful as biomarkers of Southern dietary patterns.
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http://dx.doi.org/10.1002/mnfr.202000796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192080PMC
April 2021

Regular exercise and patterns of response across multiple cardiometabolic traits: the HERITAGE family study.

Br J Sports Med 2021 Feb 22. Epub 2021 Feb 22.

Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA

Objectives: We investigated whether high responsiveness or low responsiveness to exercise training aggregates in the same individuals across seven cardiometabolic traits.

Methods: A total of 564 adults (29.2% black, 53.7% female) from the HERITAGE family study completed a 20-week endurance training programme (at 55%-75% of participants' maximal oxygen uptake (VOmax)) with VOmax, per cent body fat, visceral adipose tissue, fasting levels of insulin, high-density lipoprotein cholesterol, small low-density lipoprotein particles and inflammatory marker GlycA measured before and after training. For each exercise response trait, we created ethnicity-specific, sex-specific and generation-specific quintiles. High responses were defined as those within the 20th percentile representing the favourable end of the response trait distribution, low responses were defined as the 20th percentile from the least favourable end, and the remaining were labelled as average responses.

Results: Only one individual had universally high or low responses for all seven cardiometabolic traits. Almost half (49%) of the cohort had at least one high response and one low response across the seven traits. About 24% had at least one high response but no low responses, 24% had one or more low responses but no high responses, and 2.5% had average responses across all traits.

Conclusions: Interindividual variation in exercise responses was evident in all the traits we investigated, and responsiveness did not aggregate consistently in the same individuals. While adherence to an exercise prescription is known to produce health benefits, targeted risk factors may not improve.
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http://dx.doi.org/10.1136/bjsports-2020-103323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380259PMC
February 2021

Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk.

JCI Insight 2021 03 8;6(5). Epub 2021 Mar 8.

Cardiovascular Institute.

Recent advances in proteomic technologies have made high-throughput profiling of low-abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Furthermore, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing protein 2 (WFIKKN2) was, in turn, associated with fasting glucose, hemoglobin A1c, and HOMA-IR measurements in humans. In addition to identifying potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.
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http://dx.doi.org/10.1172/jci.insight.144392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021115PMC
March 2021

Metabolomic Profiles and Heart Failure Risk in Black Adults: Insights From the Jackson Heart Study.

Circ Heart Fail 2021 01 19;14(1):e007275. Epub 2021 Jan 19.

Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (U.A.T., D.H.K., T.Z., D.N., D.E.C., J.M.R., Z.-Z.C., B.P., M.D.B., X.S., C.S., J.G.W., R.E.G.).

Background: Heart failure (HF) is a heterogeneous disease characterized by significant metabolic disturbances; however, the breadth of metabolic dysfunction before the onset of overt disease is not well understood. The purpose of this study was to determine the association of circulating metabolites with incident HF to uncover novel metabolic pathways to disease.

Methods: We performed targeted plasma metabolomic profiling in a deeply phenotyped group of Black adults from the JHS (Jackson Heart Study; n=2199). We related metabolites associated with incident HF to established etiological mechanisms, including increased left ventricular mass index and incident coronary heart disease. Furthermore, we evaluated differential associations of metabolites with HF with preserved ejection fraction versus HF with reduced ejection fraction.

Results: Metabolites associated with incident HF included products of posttranscriptional modifications of RNA, as well as polyamine and nitric oxide metabolism. A subset of metabolite-HF associations was independent of well-established HF pathways such as increased left ventricular mass index and incident coronary heart disease and included homoarginine (per 1 SD increase in metabolite level, hazard ratio, 0.77; =1.2×10), diacetylspermine (hazard ratio, 1.34; =3.4×10), and uridine (hazard ratio, 0.79; , 3×10). Furthermore, metabolites involved in pyrimidine metabolism (orotic acid) and collagen turnover (-methylproline) among others were part of a distinct metabolic signature that differentiated individuals with HF with preserved ejection fraction versus HF with reduced ejection fraction.

Conclusions: The integration of clinical phenotyping with plasma metabolomic profiling uncovered novel metabolic processes in nontraditional disease pathways underlying the heterogeneity of HF development in Black adults.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007275DOI Listing
January 2021

MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury.

Circ Res 2021 03 6;128(5):639-651. Epub 2021 Jan 6.

Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD (C.U.O., S.J., S.M., B.L.D.-E., A.C., M.I.G., N.P., M.J.R., D.A.K.).

Rationale: The mTORC1 (mechanistic target of rapamycin complex-1) controls metabolism and protein homeostasis and is activated following ischemia reperfusion (IR) injury and by ischemic preconditioning (IPC). However, studies vary as to whether this activation is beneficial or detrimental, and its influence on metabolism after IR is little reported. A limitation of prior investigations is their use of broad gain/loss of mTORC1 function, mostly applied before ischemic stress. This can be circumvented by regulating one serine (S1365) on TSC2 (tuberous sclerosis complex) to achieve bidirectional mTORC1 modulation but only with TCS2-regulated costimulation.

Objective: We tested the hypothesis that reduced TSC2 S1365 phosphorylation protects the myocardium against IR and is required for IPC by amplifying mTORC1 activity to favor glycolytic metabolism.

Methods And Results: Mice with either S1365A (TSC2; phospho-null) or S1365E (TSC2; phosphomimetic) knockin mutations were studied ex vivo and in vivo. In response to IR, hearts from TSC2 mice had amplified mTORC1 activation and improved heart function compared with wild-type and TSC2 hearts. The magnitude of protection matched IPC. IPC requited less S1365 phosphorylation, as TSC2 hearts gained no benefit and failed to activate mTORC1 with IPC. IR metabolism was altered in TSC2, with increased mitochondrial oxygen consumption rate and glycolytic capacity (stressed/maximal extracellular acidification) after myocyte hypoxia-reperfusion. In whole heart, lactate increased and long-chain acylcarnitine levels declined during ischemia. The relative IR protection in TSC2 was lost by lowering glucose in the perfusate by 36%. Adding fatty acid (palmitate) compensated for reduced glucose in wild type and TSC2 but not TSC2 which had the worst post-IR function under these conditions.

Conclusions: TSC2-S1365 phosphorylation status regulates myocardial substrate utilization, and its decline activates mTORC1 biasing metabolism away from fatty acid oxidation to glycolysis to confer protection against IR. This pathway is also engaged and reduced TSC2 S1365 phosphorylation required for effective IPC. Graphic Abstract: A graphic abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257748PMC
March 2021

Proteomic Signatures of Lifestyle Risk Factors for Cardiovascular Disease: A Cross-Sectional Analysis of the Plasma Proteome in the Framingham Heart Study.

J Am Heart Assoc 2021 01 29;10(1):e018020. Epub 2020 Dec 29.

Boston University Department of Medicine Boston MA.

Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46±8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted value indicated statistical significance (based on number of proteins and traits tested, <4.2×10 in the discovery sample; <6.85×10 in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors.
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http://dx.doi.org/10.1161/JAHA.120.018020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955453PMC
January 2021

Mining a GWAS of Severe Covid-19.

N Engl J Med 2020 12 24;383(26):2589. Epub 2020 Nov 24.

Beth Israel Deaconess Medical Center, Boston, MA

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http://dx.doi.org/10.1056/NEJMc2025747DOI Listing
December 2020

Plasma proteomics reveals tissue-specific cell death and mediators of cell-cell interactions in severe COVID-19 patients.

bioRxiv 2020 Nov 3. Epub 2020 Nov 3.

COVID-19 has caused over 1 million deaths globally, yet the cellular mechanisms underlying severe disease remain poorly understood. By analyzing several thousand plasma proteins in 306 COVID-19 patients and 78 symptomatic controls over serial timepoints using two complementary approaches, we uncover COVID-19 host immune and non-immune proteins not previously linked to this disease. Integration of plasma proteomics with nine published scRNAseq datasets shows that SARS-CoV-2 infection upregulates monocyte/macrophage, plasmablast, and T cell effector proteins. By comparing patients who died to severely ill patients who survived, we identify dynamic immunomodulatory and tissue-associated proteins associated with survival, providing insights into which host responses are beneficial and which are detrimental to survival. We identify intracellular death signatures from specific tissues and cell types, and by associating these with angiotensin converting enzyme 2 (ACE2) expression, we map tissue damage associated with severe disease and propose which damage results from direct viral infection rather than from indirect effects of illness. We find that disease severity in lung tissue is driven by myeloid cell phenotypes and cell-cell interactions with lung epithelial cells and T cells. Based on these results, we propose a model of immune and epithelial cell interactions that drive cell-type specific and tissue-specific damage in severe COVID-19.
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http://dx.doi.org/10.1101/2020.11.02.365536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654866PMC
November 2020

Circulating testican-2 is a podocyte-derived marker of kidney health.

Proc Natl Acad Sci U S A 2020 10 21;117(40):25026-25035. Epub 2020 Sep 21.

Nephrology Division, Massachusetts General Hospital, Boston, MA 02114;

In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort ( = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort ( = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, , exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.
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http://dx.doi.org/10.1073/pnas.2009606117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547280PMC
October 2020

Metabolomic signatures of cardiac remodelling and heart failure risk in the community.

ESC Heart Fail 2020 Sep 10. Epub 2020 Sep 10.

NHBLI and Boston University's Framingham Heart Study, Framingham, MA, USA.

Aims: Heart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community.

Methods And Results: We assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross-sectionally and to incident HF prospectively. Bonferroni-adjusted P-values <0.05 denoted statistical significance. Circulating concentrations of kynurenine [β = -0.12 cm per standard deviation (SD) increment in normalized residual of metabolite, P = 7.3 × 10 ] and aminoadipate (-0.11 cm per SD increment, P = 2.61 × 10 ) were associated with left ventricular diastolic dimension, phosphatidylcholine (carbon:double bound = 38:6) with left atrial dimension (0.10 cm per SD increment, P = 9.7 × 10 ), and cholesterol ester (carbon:double bound = 20:5) with left atrial dimension (0.10 cm per SD increment, P = 1.4 × 10 ) in multivariable-adjusted models. During an average follow-up of 15.8 (range 0.02-23.2) years, 113 participants (5%) were diagnosed with HF with reduced ejection fraction and 106 individuals (5%) with HF with preserved ejection fraction. In multivariable analyses, concentrations of phosphatidylcholine (hazard ratio 0.63, P = 1.3 × 10 ) and ornithine (hazard ratio 1.44, P = 0.00014) were associated with HF with reduced ejection fraction.

Conclusions: Several metabolites, including the vasoactive metabolite kynurenine, were related to cardiac structure and function in our sample. Additional research is warranted to confirm our observations and investigate if these metabolites can risk stratify ambulatory individuals.
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http://dx.doi.org/10.1002/ehf2.12923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754777PMC
September 2020

Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress.

Clin Sci (Lond) 2020 09;134(17):2369-2379

Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A.

Objective: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction.

Methods: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release.

Results: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and β-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, β-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05).

Conclusions: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.
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http://dx.doi.org/10.1042/CS20191227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176641PMC
September 2020

The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

Nat Commun 2020 07 13;11(1):3479. Epub 2020 Jul 13.

Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.
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http://dx.doi.org/10.1038/s41467-020-17254-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359028PMC
July 2020

Proteomic Profiling in Biracial Cohorts Implicates DC-SIGN as a Mediator of Genetic Risk in COVID-19.

medRxiv 2020 Jun 11. Epub 2020 Jun 11.

COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear. Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.31 locus. To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in the ABO locus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses, as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine. Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.
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http://dx.doi.org/10.1101/2020.06.09.20125690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302224PMC
June 2020

Proteomic and Metabolomic Correlates of Healthy Dietary Patterns: The Framingham Heart Study.

Nutrients 2020 May 19;12(5). Epub 2020 May 19.

Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.

Data on proteomic and metabolomic signatures of healthy dietary patterns are limited. We evaluated the cross-sectional association of serum proteomic and metabolomic markers with three dietary patterns: the Alternative Healthy Eating Index (AHEI), the Dietary Approaches to Stop Hypertension (DASH) diet; and a Mediterranean-style (MDS) diet. We examined participants from the Framingham Offspring Study (mean age; 55 years; 52% women) who had complete proteomic ( = 1713) and metabolomic ( = 2284) data; using food frequency questionnaires to derive dietary pattern indices. Proteins and metabolites were quantified using the SomaScan platform and liquid chromatography/tandem mass spectrometry; respectively. We used multivariable-adjusted linear regression models to relate each dietary pattern index (independent variables) to each proteomic and metabolomic marker (dependent variables). Of the 1373 proteins; 103 were associated with at least one dietary pattern (48 with AHEI; 83 with DASH; and 8 with MDS; all false discovery rate [FDR] ≤ 0.05). We identified unique associations between dietary patterns and proteins (17 with AHEI; 52 with DASH; and 3 with MDS; all FDR ≤ 0.05). Significant proteins enriched biological pathways involved in cellular metabolism/proliferation and immune response/inflammation. Of the 216 metabolites; 65 were associated with at least one dietary pattern (38 with AHEI; 43 with DASH; and 50 with MDS; all FDR ≤ 0.05). All three dietary patterns were associated with a common signature of 24 metabolites (63% lipids). Proteins and metabolites associated with dietary patterns may help characterize intermediate phenotypes that provide insights into the molecular mechanisms mediating diet-related disease. Our findings warrant replication in independent populations.
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http://dx.doi.org/10.3390/nu12051476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284467PMC
May 2020

Metabolomics and Proteomics in Type 2 Diabetes.

Circ Res 2020 05 21;126(11):1613-1627. Epub 2020 May 21.

Cardiovascular Institute (Z.-Z.C., R.E.G.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.

The persistent increase in the worldwide burden of type 2 diabetes mellitus (T2D) and the accompanying rise of its complications, including cardiovascular disease, necessitates our understanding of the metabolic disturbances that cause diabetes mellitus. Metabolomics and proteomics, facilitated by recent advances in high-throughput technologies, have given us unprecedented insight into circulating biomarkers of T2D even over a decade before overt disease. These markers may be effective tools for diabetes mellitus screening, diagnosis, and prognosis. As participants of metabolic pathways, metabolite and protein markers may also highlight pathways involved in T2D development. The integration of metabolomics and proteomics with genomics in multiomics strategies provides an analytical method that can begin to decipher causal associations. These methods are not without their limitations; however, with careful study design and sample handling, these methods represent powerful scientific tools that can be leveraged for the study of T2D. In this article, we aim to give a timely overview of circulating metabolomics and proteomics findings with T2D observed in large human population studies to provide the reader with a snapshot into these emerging fields of research.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315898DOI Listing
May 2020

Aptamer-Based Proteomic Platform Identifies Novel Protein Predictors of Incident Heart Failure and Echocardiographic Traits.

Circ Heart Fail 2020 05 15;13(5):e006749. Epub 2020 May 15.

Framingham Heart Study, Framingham, MA (M.N., M.G.L, R.S.V).

Background: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals.

Methods: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia.

Results: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (<3.8×10; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (=0.001).

Conclusions: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236427PMC
May 2020

Comparison of Proteomic Assessment Methods in Multiple Cohort Studies.

Proteomics 2020 06;20(12):e1900278

Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908.

Novel proteomics platforms, such as the aptamer-based SOMAscan platform, can quantify large numbers of proteins efficiently and cost-effectively and are rapidly growing in popularity. However, comparisons to conventional immunoassays remain underexplored, leaving investigators unsure when cross-assay comparisons are appropriate. The correlation of results from immunoassays with relative protein quantification is explored by SOMAscan. For 63 proteins assessed in two chronic obstructive pulmonary disease (COPD) cohorts, subpopulations and intermediate outcome measures in COPD Study (SPIROMICS), and COPDGene, using myriad rules based medicine multiplex immunoassays and SOMAscan, Spearman correlation coefficients range from -0.13 to 0.97, with a median correlation coefficient of ≈0.5 and consistent results across cohorts. A similar range is observed for immunoassays in the population-based Multi-Ethnic Study of Atherosclerosis and for other assays in COPDGene and SPIROMICS. Comparisons of relative quantification from the antibody-based Olink platform and SOMAscan in a small cohort of myocardial infarction patients also show a wide correlation range. Finally, cis pQTL data, mass spectrometry aptamer confirmation, and other publicly available data are integrated to assess relationships with observed correlations. Correlation between proteomics assays shows a wide range and should be carefully considered when comparing and meta-analyzing proteomics data across assays and studies.
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http://dx.doi.org/10.1002/pmic.201900278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425176PMC
June 2020
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