Framingham Project/Levy

National Heart, Lung, And Blood Institute

Investigators

Linked publications, trials & patents

Abstract

As part of the Population Sciences Branch (PSB), the Levy Lab conducts genetic and multidimensional omics research focused on cardiovascular disease (CVD) and its risk factors. Two important areas of the Levy Lab's intramural research are: 1) blood pressure (BP) genetics 2) multidimensional omics of BP and CVD The Levy Lab leverages the genotype and phenotype resources of the Framingham Heart Study (FHS) as well as NIH intramural resources including NHLBI's DNA Sequencing and Genomics Core Laboratory, CIT's Mathematical and Statistical Computing Laboratory, and NCBI's Computational Biology and Informational Engineering Branches. Goals for the PSB and Levy Lab: Goal 1: Identify genetic contributions to BP. Hypertension affects 80 million adults in the U.S. and it is a major contributor to multiple forms of CVD including coronary heart disease (CHD), stroke, and heart failure. Dr. Levy's research in hypertension focuses on cross-cutting studies of its genetic, transcriptomic, and epigenetic underpinnings. To advance research in the area of BP genetics, Dr. Levy leads or co-leads several large BP consortium working groups. The results of Dr. Levy's research provide clues to novel genes and pathways involved in BP regulation and highlight potential therapeutic targets for the treatment of hypertension and the prevention of its sequelae. Goal 2: Apply multidimensional omics to identify biomarker signatures of BP and CVD related conditions. Identifying novel CVD biomarkers has important implications for understanding disease biology and developing targeted prevention strategies in the preclinical phase of CVD when intervention is most likely to be effective. Discovering highly predictive biomarkers of CVD risk could represent a breakthrough for risk stratification if this approach improves upon current risk assessment methods. Most recently PSB initiated four new research programs: 1. RAGE/sRAGE axis research 2. Conduct state of the art RNA Sequencing in over 1300 Framingham Participants (Part of NHLBI's TOPMed Program) 3. The Role of COVID 4. Proteomics programs: 4a: Proteomics Biomarkers of the risk of developing Heart Failure 4b: Protein biomarkers of chronic obstructive pulmonary disease and its progression 4c: Scallop Consortium: We are active members of the Scallop Consortium 1. Rage/sRage Axis: Elevated mRAGE levels in human sputum samples have been observed in asthmatic patients relative to healthy controls. mRAGE has also been shown to be a critical component in allergen-induced asthma and airway inflammation in Ager knockout mouse models. In contrast, lower levels of sRAGE have been observed in asthmatic patients and in the bronchoalveolar lavage fluid of asthma-induced mice compared to healthy controls. But the role of the AGER-mRAGE-sRAGE axis as a directly causal or protective pathway for asthma remains unclear. New research from Dr. Levys lab reveals a causal role of the AGER-mRAGE-sRAGE axis in asthma in humans and suggests a strategy for using antisense oligonucleotides (ASOs) to generate an alternatively spliced RAGE protein that lacks the transmembrane domain that binds RAGE protein to the cell membrane and will generate more unbound vs. membrane-bound protein, resulting in a greater sRAGE-to-mRAGE ratio. Dr. Levys lab proposes that this greater ratio will be protective against inflammation in the lung. 2. RNA Sequencing The primary aim RNA Sequencing will be the identification of expression quantitative trait loci (eQTLs) genome wide via the alignment of whole genome DNA sequencing and RNA sequencing. This approach will also permit the assessment of allele specific expression genome wide and alternative splicing QTLs (sQTLs) genome wide. These data are ready for analysis by both TOPMed investigators through the dbGaP data exchange portal and by PSB staff utilizing a cloud computing structure. 3. COVID-19 Efforts (SARS-CoV-2, severe acute respiratory syndrome coronavirus 2) The Levy lab will conduct a complex multi-omics exploration of molecular precursors of COVID-19 susceptibility and severity by measuring protein biomarkers of dysregulated immune response and inflammation and conducting integrative genomics analyses and causal inference testing. Available omics resources from the FHS include whole genome sequencing, transcriptomics, proteomics, and DNA methylation on thousands of FHS participants. We propose to measure 340 key proteins involved in immune response and inflammation, including scores of cytokines and chemokines that characterize the cytokine storm, which transforms COVID-19 infection into severe life-threatening disease. These proteins will be integrated with existing phenotypes, genotypes, and omics data to identify causal genes, proteins, and pathways that contribute to COVID-19 susceptibility and severity. We posit that our approach to unraveling underlying causal mechanisms of disease will prove useful in developing targeted drug therapies for COVID-19. 4. Proteomics Programs 4a: Proteomics Biomarkers of the risk of developing Heart Failure: We initiated a project collaboration with ARIC, FHS and HOMAGE and will focus on proteomic targets. The collaboration will expand discovery efforts and allow cross-replicating results of previously found, but unvalidated individual project level data. It will also take advantage of the ethnic diversity and multiple comorbidities in the merged cohorts so as to investigate the interaction between sex, race, and co-morbidities with the proteomic predictors of HF. Aim: Identify the differential proteomic biomarker profiles in patients who have experienced an incident HF event. 4b: PSB has embarked on a proteomics study to identity biomarkers of COPD. Chronic obstructive pulmonary disease (COPD) was the seventh leading cause of early death globally in a 2017 study of global burdens of disease, rising in the ranks from the eleventh cause of early death in 1990. Due to an aging population and prolonged exposure to environmental risk factors, global COPD prevalence is projected to increase in the next decade. Given the paucity of clinically useful COPD biomarkers and the scarcity of population-based studies, identifying predictive COPD biomarkers would help discern high-risk individuals who may benefit from early preventive therapies. Furthermore, biomarkers of COPD progression may provide insights into causal mechanisms for the disease and provide insight into new therapies Purpose/Aims 1. Identify proteomic biomarkers of prevalent COPD (using GOLD Stage 2 criteria). 2. Identify proteomic biomarkers of new-onset COPD. 3. Identify proteomic biomarkers of continuous measures of lung function cross-sectionally and of their changes longitudinally. 4c: Scallop Consortium: The SCALLOP consortium members aim to collaborate to identify novel genetic determinants for plasma protein concentrations measured using the Olink PEA technology. The basic assumption is that each of the participating members are PIs (or closely connected to PIs) of human sample collections in which analyses of plasma proteins using the Olink PEA technology and genome-wide genotyping have been performed. The consortium members will share summary statistics from genome-wide SNP association analyses of plasma protein concentrations in the respective participating study collection with the intention of analyzing data jointly for the discovery of genetic loci linked to plasma protein concentrations. In the past year, PSB has made several recent advances in analysis of multidimensional omics data including: discovery and targeted proteomics of CHD, transcriptomic and systems biology analyses of BP and CHD, DNA methylation signatures of BP, and integrative genomic approaches to identify mechanisms underlying CVD traits and promising therapeutic targets fo