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 focused on 3 research programs: 1. Inflammatory biomarker research 2. Conduct state of the art RNA Sequencing in over 1300 Framingham participants (in conjunction with NHLBI's TOPMed Program) 3. Proteomics programs: Protein biomarkers of chronic lung disease 1. Rage/sRage Axis: Low plasma sRAGE levels have been observed in asthmatic patients relative to healthy controls. Lower levels of sRAGE have been observed in the bronchoalveolar lavage fluid of asthma-induced mice compared to healthy controls. New research from Dr. Levy's lab reveals a causal role of the AGER-mRAGE-sRAGE axis in asthma and chronic lung disease in humans and suggests a strategy for targeting this pathway as a means to prevent or treat asthma and smoking-related lung inflammation. The experimental treatment that we are testing reduces levels of mRAGE and increases expression of sRAGE. We posit that this strategy will have the dual effect of increasing the anti-inflammatory properties and reducing the pro-inflammatory properties of the RAGE proteins. For the purposes of establishing a murine model, we have selected to separate our sample size into three separate treatment arms: A) Mice treated with intervention, then sensitized and challenged with allergen Treatment+ // OVA + B) Mice treated with placebo, then sensitized and challenged with allergen Treatment - // OVA + C) Mice not treated, then sensitized and challenged with phosphate buffered saline Treatment - // OVA - We have completed the laboratory work (animal lab) on this study and are in the process of analyzing the data. We are still waiting on some of the data as histopathology can take some time to generate. We are working towards a manuscript and waiting on the final few pieces to determine if they should be included in the paper or not. 2. RNA Sequencing The primary aim RNA Seq will be the identification of expression quantitative trait loci (eQTLs) genome wide via the alignment of whole genome DNA seq and RNA seq. 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 TOPMed investigators through the dbGaP data exchange portal and by PSB staff utilizing a cloud computing structure. 3. Proteomics Programs PSB has embarked on a proteomics study to identity biomarkers of chronic obstructive lung disease (COPD). 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 lack 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 prevalent restrictive lung disease. 3. Identify proteomic biomarkers of continuous measures of lung function. 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 We will add a new program in 2024 as we should receive Grant funding for a grant titled: The Dynamic Nuclear and Mitochondrial Genomes. A phenomenon that exemplifies the dynamic nature of the nuclear genome is clonal hematopoiesis of indeterminate potential (CHIP). CHIP is the age-related acquisition and clonal expansion of hematopoietic-derived cells that harbor functional somatic mutations in whole blood; these mutations confer a fitness advantage to the mutated hematopoietic stem cell. Observational studies have found that CHIP is associated with an increased risk for hematologic malignancies, coronary artery disease, ischemic stroke, chronic lung disease, and all-cause mortality. Murine models and cell-based studies suggest that dysregulated inflammatory signaling conferred by certain driver gene mutations may be a mechanism linking CHIP to adverse outcomes. A single cell can contain hundreds to thousands of mitochondria and each mitochondrion can harbor multiple copies of the mitochondrial genome. As a result, mutations can affect all mitochondrial DNA copies in a cell, known as homoplasmy, or a subset of them, known as mitochondrial heteroplasmy (MH). High depth sequencing has shown that MH accumulates with age, suggesting that the acquisition and expansion of de novo mitochondrial mutations may contribute to accelerated aging. Deleterious mutations exceeding a frequency threshold can impair mitochondrial function and result in disease. Another dynamic feature of the mitochondrial genome is change in mitochondrial copy number (mtCN), which declines in an age-dependent manner. Substantial reduction in mtCN impairs cellular energy production capacity. Observational studies have linked MH and reduced mtCN to cardiovascular disease (CVD), CVD risk factors, and all-cause mortality. This Population Sciences Award proposes a work scope covering the following major themes i) conducting analyses of the clinical and molecular signatures of prevalent CHIP, MH, and mtCN, and ii) repeating WGS on 2500 FHS and 1500 JHS participants to document de novo CHIP and MH and characterize their clinical and molecular determinants. WGS will be conducted by a Trans-Omics for Precision Medicine (TOPMed) program laboratory using established TOPMed me