Project 1 Proteomics and Metabolomics SABRe CVD Project 1 has completed data collection to and now is in the analysis phase. The only lab work currently under way is replication studies based on the initial proteomics/metabolomics analyses. Available data resources generated by SABRe Project 1 are: 1. CVD sample set (336 case/control pairs (135MI C/C subset) total n=672) a. iTRAQ proteomics on 135 FHS MI case/control matched pairs b. Targeted LC/MS-MRM on 32 proteins on full CVD data set c. Targeted LC/MS Depletion-MRM on 28 proteins on full CVD data set 2. Metabolic Syndrome Factorial study set (n=652 samples) a. iTRAQ proteomics on 160 sample from factorial design study b. Targeted LC/MS-LIPDS MRM on 154 lipid species c. Targeted GC/MS on 155 metabolites on 670 individuals d. Replication of top 37 GC/MS metabolites in 650 samples from the BioImage Replication study On-going analysis: 1. The SABRe analysis team has submitted a proteomics paper titled Protein Biomarkers of New-Onset Cardiovascular Disease: A Prospective Study from the Systems Approach to Biomarker Research in Cardiovascular Disease (SABRe CVD) Initiative. As part of the Systems Approach to Biomarker Research in Cardiovascular Disease (SABRe CVD) Initiative, which seeks to discover biomarkers of ASCVD and its major risk factors, we sought to identify plasma protein biomarkers of new-onset myocardial infarction (MI) and ASCVD in participants from the Framingham Heart Study (FHS). Identification of novel biomarkers that individually or aggregately predict risk of ASCVD could provide insight into the biology of the disease and could aid in developing targeted prevention strategies during the preclinical phase of ASCVD, when intervention may be more likely to alter disease progression. In this paper, in conjunction is SABRe Project 2, we report on the proteomics profiling analyses having identified single and multimarker protein panels that are associated with new onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD. 2. The SABRe analysis team has submitted a metabolomics paper titled Discovery and Independent Replication of Metabolomic Signatures of Metabolic Risk Factors. Here we report on the SABRe efforts that have identified multiple metabolomic biomarkers of metabolic risk factors including glutamic acid and other metabolites involved in the Krebs cycle whose levels are mediated by transaminase reactions. Understanding the pathways represented by our results may help unravel molecular derangements contributing to metabolic syndrome and its risk factors 3. Draft publication on Lipid LC/MS analysis is in late writing stage and should be submitted for publication by the end of 2013. SABRe CVD Project 2Targeted Protein Immunoassays 1. To date the contractor has completed measurements of 55 proteins in 8 different multiplex panels on over 7300 Framingham samples. All of these data sets are available in dbGaP. 2. We have 3 additional panels with a total of 10 additional makers in-progress. Their multiplex panels have been fully developed and are actively being measured in the lab. 3. There are 16 markers (two additional panels) in advanced assay development and these will become production assays in October, 2013. 4. Sixty additional protein biomarkers targets have been nominated and are in the initial assay development process where antibodies and commercial reagent availability are being assessed. On-going analysis: 1. The aforementioned proteomics publication integrates the initial ASCVD analysis of the first 50 markers from SABRe project 2. 2. An analysis pipeline exists to rapidly conduct analysis on each biomarker in association with all-cause mortality, CVD, and CHD on the new assay panels once they complete the data collection and QC stages. SABRe CVD Project 3Gene Expression (mRNA) Analysis The SABRe CVD gene expression data resource created by Project 3 is completed and includes genome-wide transcriptomic profiling using the Affymetrix array 1.0 ST on approximately 5800 Framingham participant samples from the Offspring exam 8 and Third generation exam two cohorts. On-going analysis: 1. The SABRe Project 3 analysis team is coordinating several different data analysis projects using the data set. The table below includes some of the various research projects utilizing the data resources. They are at varying points in their analysis plans. SABRe # Project Title SB-001 Genetic correlates of Gal-3 in the community SB-002 Initial Gene Expression analysis of Offspring Cohort SB-003 Genomics of IgE Dysregulation SB-004 Gene Expression with Atrial Fibrualtion and PR Interval SB-005 Vascular Function and Gene expression SB-006 Systems Biology study of Blood Pressure SB-008 Sex-specific and Age-related miRNA-mRNA networks SB-010 Smoking and Gene Expression SB-011 Gene expression signature of circulating naturatic Peptide levels SB-012 Gene Expression signature of SDF-1 SB-013 Genomics of Glycemic Traits SB-014 Genomics of COPD/Chroinc Airflow Obstruction SB-015 Gene expression profiling for Bone Mineral Density Measured by Dual Energy X-ray Absorptiometry SB-016 Copy number variation of gene expression SB-017 A systematic study of heritability of gene expression and analysis of mRNA / miRNA eQTLs SB-019 CVD-miRNA systems approach SB-021 A systematic study of heritability of gene expression and analysis of mRNA / miRNA eQTLs SB-022 HRT and gene expression SB-023 Co-expression networks of lipid traits SB-024 Gene expression with echocardiographic traits SB-028 Lipid GWAS cis-eQTLs in whole blood SB-029 Systems Biology study of Blood Pressure SB-031 Gene expression with age-related inflammation SB-032 FOXO3A gene networks and aging SB-033 eQTL on 1000G for SABRe SB-034 Gene expression confirmation of lipid GWAS signals SB-035 Influence of dietary fat intake on gene expression and plasma lipid levels SABRe CVD Project 4-miRNA Profiling The data resource for SABRe CVD Project 4 is also completed. We completed measurement of 350 miRNA across 5800 Offspring and Third Generation cohort participant samples. All data are available in dbGaP. On-going analysis: 1. The SABRe Project 4 analysis team has several cross over projects with the Project 3 team as these compromise the systems biology approaches of SABRe. The table below is some of the SABRe Research proposals making use of the Project 4 data resource. SABRe # Project Title SB-003 Genomics of IgE Dysregulation SB-004 Gene Expression with Atrial Fib and PR Interval SB-008 Sex-specific and Age-related miRNA-mRNA networks SB-012 Gene Expression signature of SDF-1 SB-013 Genomics of Glycemic Traits SB-014 Genomics of COPD/Chronic Airflow Obstruction SB-017 A systematic study of heritability of gene expression and analysis of mRNA / miRNA eQTLs SB-019 CVD-miRNA systems approach SB-021 A systematic study of heritability of gene expression and analysis of mRNA / miRNA eQTLs SB-024 Gene expression with echocardiographic traits SB-028 Lipid GWAS cis-eQTLs in whole blood SB-029 Systems Biology study of Blood Pressure SB-031 Gene expression with age-related inflammation SB-034 Gene expression confirmation of lipid GWAS signals

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$1,515,471
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Paul, Ligi; Jacques, Paul F; Aviv, Abraham et al. (2015) High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort. Eur J Nutr 54:235-41
Yin, Xiaoyan; Subramanian, Subha; Hwang, Shih-Jen et al. (2014) Protein biomarkers of new-onset cardiovascular disease: prospective study from the systems approach to biomarker research in cardiovascular disease initiative. Arterioscler Thromb Vasc Biol 34:939-45
Goff Jr, David C; Lloyd-Jones, Donald M; Bennett, Glen et al. (2014) 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129:S49-73
Ho, Jennifer E; Yin, Xiaoyan; Levy, Daniel et al. (2014) Galectin 3 and incident atrial fibrillation in the community. Am Heart J 167:729-34.e1
Subramanian, Subha; Liu, Chunyu; Aviv, Abraham et al. (2014) Stromal cell-derived factor 1 as a biomarker of heart failure and mortality risk. Arterioscler Thromb Vasc Biol 34:2100-5
Goff Jr, David C; Lloyd-Jones, Donald M; Bennett, Glen et al. (2014) 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 63:2935-59
Sinner, Moritz F; Stepas, Katherine A; Moser, Carlee B et al. (2014) B-type natriuretic peptide and C-reactive protein in the prediction of atrial fibrillation risk: the CHARGE-AF Consortium of community-based cohort studies. Europace 16:1426-33
Peloso, Gina M; Auer, Paul L; Bis, Joshua C et al. (2014) Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. Am J Hum Genet 94:223-32
McManus, David D; Lin, Honghuang; Tanriverdi, Kahraman et al. (2014) Relations between circulating microRNAs and atrial fibrillation: data from the Framingham Offspring Study. Heart Rhythm 11:663-9
Grove, Megan L; Yu, Bing; Cochran, Barbara J et al. (2013) Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. PLoS One 8:e68095

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