The Value of Omics in Cardiovascular Research: Getting More Comfortable, More Frustrated or More Curious

Transcription

1 The Value of Omics in Cardiovascular Research: Getting More Comfortable, More Frustrated or More Curious Daniel Levy, MD Framingham Heart Study Population Sciences Branch National Heart, Lung, and Blood Institute American College of Cardiology 47 th Annual New York Cardiovascular Symposium December 12, 2014

2 Traditional Biomarker Strategies for CVD Prevention Traditional biomarker strategies for CVD prevention are based on understanding risk factor contributions to the biology of CVD Basic science Population science Large-scale clinical trials of interventions These approaches work but have been slow and are poorly integrated

3 Traditional Biomarker Strategies for CVD Prevention: Cholesterol as a Target Basic science 1859: Rudolf Virchow described the microscopic appearance of atheroma. 1904: International Congress of Pathology understood that cholesterol esters comprised the core of the atherosclerotic plaque. 1913: Nicolai Anitschkow fed rabbits purified cholesterol and produced atherosclerosis.

4 Traditional Biomarker Strategies for CVD Prevention: Cholesterol as a Target Population science and clinical trials 1940s: Ancel Keys studied patterns of fat and cholesterol in the diet in 7 countries. 1961: Framingham identified cholesterol as a factor of risk for CHD. 1984: LRC-CPPT Trial provided evidence that cholesterol lowering reduces CHD risk. 1987: Lovastatin approved by FDA 1990s-2000s: Serial clinical trials proved that lower LDL is better. It has taken 150 years to get to this point!

5 Future Strategies for CVD Prevention Future strategies for CVD prevention will be technology-driven Genetics and genomics Proteomics, metabolomics, and lipomics Bioinformatics, systems biology, and data mining Will be integrated to rapidly identify causal risk factors for CVD

6 The SABRe CVD Initiative SABRe CVD: Systems Approach to Biomarker Research in Cardiovascular Disease Aim: To identify biomarker signatures of atherosclerotic CVD and its risk factors using cutting-edge omic technologies To accelerate biomarker discovery through omic technologies

7 The SABRe CVD Initiative Accelerating Discovery Through Omics Technology Overview of the SABRe CVD Initiative Metabolomic signatures of metabolic risk factors Transcriptomic signatures of metabolic risk factors Proteomic signatures of CVD

8 The SABRe CVD Initiative Accelerating Discovery Through Omics Technology Overview of the SABRe CVD Initiative Metabolomic signatures of metabolic risk factors Transcriptomic signatures of metabolic risk factors Proteomic signatures of CVD

9 SABRe CVD Initiative: Four Integrated Biomarker Projects Project 1: Discovery proteomics and metabolomics Project 2: Targeted immunoassays of plasma proteins Project 3: Gene expression profiling Project 4: microrna profiling Proteome/metabolome Immunoassays Transcriptome mirna

10 The SABRe CVD Initiative Accelerating Discovery Through Omics Technology Overview of the SABRe CVD Initiative Metabolomic signatures of metabolic risk factors Transcriptomic signatures of metabolic risk factors Proteomic signatures of CVD

11 Metabolomic Signatures of Metabolic Risk Factors: Background Multiple cardiovascular disease (CVD) risk factors cluster in the same individuals Their concurrence is used to diagnose metabolic syndrome, which carries substantial risk for CVD We hypothesized that metabolic risk factors are associated with multiple metabolomic derangements Proteome/metabolome

12 Metabolomic Signatures of Metabolic Risk: Aims We conducted a two-phase experiment using gas chromatography-mass spectrometry (GC/MS) profiling to identify metabolomic signatures of metabolic risk factors Obesity Dyslipidemia Dysglycemia Discovery in the Framingham Heart Study Replication in BioImage Study (V. Fuster, PI) Proteome/metabolome

13 Metabolite Associations with Metabolic Risk Factors Obesity 4 Dyslipidemia Dysglycemia Proteome/metabolome

14 The SABRe CVD Initiative Accelerating Discovery Through Omics Technology Overview of the SABRe CVD Initiative Metabolomic signatures of metabolic risk factors Transcriptomic signatures of metabolic risk factors Proteomic signatures of CVD

15 Transcriptomic Signatures of Metabolic Risk Factors: Aims We conducted a transcriptomic study of mrna signatures of metabolic risk factors Framingham Offspring Participants Whole blood RNA (PaxGene Tubes) mrna expression: Affymetrix Human Exon Array Gene Expression

16 Transcriptomic Signatures of Metabolic Risk Factors Transcriptome

17 Transcriptomic Signatures of CHD Transcriptome

18 The SABRe CVD Initiative Accelerating Discovery Through Omics Technology Overview of the SABRe CVD Initiative Metabolomic signatures of metabolic risk factors Transcriptomic signatures of metabolic risk factors Proteomic signatures of CVD

19 Identifying Novel Protein Biomarkers of CVD Risk Current CVD risk assessment methods are imperfect; many high risk individuals are not detected prior to the onset of clinical disease We hypothesized that a highly predictive panel of diagnostic protein biomarkers can improve upon event prediction over and above established clinical CVD risk factors Identifying high risk individuals very early in the course of atherosclerosis progression will allow for initiation of preventive approaches when they are most likely to be successful Immunoassays

20 Proteomic Platforms Discovery proteomics using mass spectrometry Targeted proteomics via immunoassays Immunoassays

21 Discovery Proteomics Biomarkers of MI Yin X, et al. Arterioscler Thromb Vasc Biol Apr;34(4):

22 Protein Multimarker Panel for ASCVD Protein HR 95% CI P-Value Ceruloplasmin , Growth differentiation factor , Lipoprotein(a) , Tissue inhibitor of metalloproteinases , Levy D. et al. American Heart Association Scientific Sessions, 2013.

23 Population Research Personalized Medicine Data collection Biorepository Genome Genetic Gene Variation Expression Clinical Disease Circulating Biomarkers Systems Biology Transcriptome Proteome/metabolome

24 SABRe CVD Initiative: Future Implications In-depth study of biomarkers of atherosclerosis and metabolic risk factors will provide additional insights into the pathogenesis of cardiovascular disease Promote development of new diagnostic tests for personalized medicine Advance understanding of the biology of health and disease - Identify new therapeutic targets - Create a pipeline for new drugs to treat and prevent disease

25 Deaths from Heart Disease and Stroke in the US Deaths/100, CHD -61% Stroke -69%

26 The SABRe CVD Initiative Project 1 Project 2 Project 3 Project 4 Data and Informatics Marty Larson Tarjinder Singh Chris O Donnell Jane Freedman Andrew Johnson Pieter Muntendam Emelia Benjamin Peter Munson Martin Larson Karen Mutalik Neal Gordon Caroline Fox Nalini Raghavachari Andrew Johnson Ken Nieto Chris O Donnell Dian Er Chen Tianxiao Huan Chris O Donnell David Lipman Caroline Fox Marty Larson Jane Freedman Shih-Jen Hwang Tarjinder Singh Sandy Robbins Sandy Robbins Andrew Johnson Kahraman Tanriverdi Mike Feolo Shih-Jen Hwang Ralph D Agostino Roby Joehanes Jian Rong Peter Munson Xiaoyan Yin Subha Subramanian Marty Larson Tianxiao Huan Roby Joehanes Subha Subramanian R.S. Vasan Sai-Xia Ying Chen Yao Tanya Barrett Brian Chen Joe Massaro Nancy Heard-Costa And many more to join

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