Framingham Project/Levy

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

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. Three important areas of the Levy Lab's intramural research are: 1) Multi-omics investigation of BP and CVD 2) Dynamic changes over time in the nuclear and mitochondrial genomes The Levy Lab leverages the vast genomic 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 molecular contributions to CVD. 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 focuses on cross-cutting studies of the genetic, transcriptomic, and epigenetic underpinnings of CVD and its risk factors. To advance research in the molecular contributions to CVD, Dr. Levy leads or co-leads several large working groups. The results of Dr. Levy's research provide clues to novel genes and pathways involved in CVD risk and highlight potential therapeutic targets for treatment and the prevention of its sequelae. Goal 2: Conduct repeat whole genome sequencing (WGS) on FHS and Jackson Heart Study (JHS) participants to document de novo nuclear and mitochondrial mutations, including clonal hematopoiesis and mitochondrial heteroplasmy and their clinical and molecular determinants. WGS will be conducted by a Trans-Omics for Precision Medicine (TOPMed) program laboratory using established TOPMed methods. Analyses will be conducted by the study team that can point toward causal mechanisms of diseases linked to somatic mutations. Most recently, PSB research has been focused on 4 research areas: 1. Inflammatory biomarker research 2. State-of-the art RNA sequencing of FHS participants (in conjunction with NHLBI's TOPMed Program) 3. Proteomics programs using OLINK proteomics platform 4. Repeat WGS to identify de novo somatic mutations • 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. • Proteomics Programs There are several efforts to utilize proteomics data to further the understanding of complex disease. Using available proteomics data obtained by the Levy lab in conjunction with TOPMed data proteomics and UK Biobank proteomic data, the Levy Lab is characterizing proteomic biomarkers of lung disease, hypertension, and diabetes. In a recently publish paper, we looked at lung function data. Respiratory disorders, including chronic obstructive and restrictive lung diseases, rank among the leading global causes of premature death. A variety of factors including inflammation, infection, genetic susceptibility, aging, and exposure to tobacco smoke and environmental pollutants profoundly impact the structural integrity and functional capacity of the lungs and airways. These lung-associated pathologies often coexist with other comorbidities. Spirometry, a cornerstone for assessing lung function, quantifies lung volumes such as forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC). Numerous studies have underscored the independent association of diminished FEV1 and FVC with increased risks for cardiovascular diseases, metabolic syndrome, and various malignancies. Chronic obstructive pulmonary disease (COPD), owing to its irreversible nature, carries the greatest toll of mortality and disability among chronic lung diseases. Concurrently, chronic restrictive lung diseases, including interstitial lung diseases and sarcoidosis, also contribute substantially to mortality and disability. The burden of chronic respiratory diseases is projected to rise, largely due to aging of the population, creating an urgent need to identify mechanisms underlying these diseases. The paucity of diagnostic biomarkers for early detection of lung disease and limited understanding of causal mechanisms needed to target novel treatments have spurred a widespread search for biomarkers of lung function and respiratory diseases. The screening of plasma proteins has emerged as a promising strategy to identify candidate diagnostic biomarkers of disease and provide a deeper understanding of disease pathophysiology. While previous studies have identified several protein biomarkers of COPD, individual biomarkers account for only a fraction of overall disease risk. High-throughput proteomic panels permit more comprehensive identification of disease-risk biomarkers. We hypothesized that exploring a large panel of proteins would reveal biomarkers of spirometry traits that could provide molecular insights into disease mechanisms. To this end, we conducted an association study of nearly 3000 plasma proteins with continuous measures of lung function, and with obstructive and restrictive spirometry patterns (OSP, RSP) in 32,493 UK Biobank (UKB) participants. We validated our findings in 740 participants from the Framingham Heart Study (FHS) and employed Mendelian randomization (MR) analyses to infer causal relations of protein biomarkers to spirometry traits. In the past year, the Levy Lab has made several recent advances in analysis of multidimensional omics data including discovery and targeted proteomics, transcriptomic, epigenetics, and integrative multi-omics approaches to analyses to identify molecular mechanisms underlying CVD traits.