Rare monogenic forms of common diseases have provided key fundamental insights about common disease. However, genetic, environmental, and stochastic elements influence risk for disease. Familial hypercholesterolemia (FH), an autosomal dominant disorder afflicting 1 in 250 linked to severe increases in LDL cholesterol and premature coronary heart disease (CHD) risk, is an ideal model to characterize modifiers of disease. Despite the presence of a strong genetic driver of hypercholesterolemia from FH mutations, we recently observed that half do not have the expected severe hypercholesterolemia. In this proposal, we outline several methods to discover and dissect the genetic and non-genetic factors influencing CHD risk conferred by FH mutations in humans and determine whether knowledge of these factors can improve risk discrimination among those with FH mutations. Our approach harnesses several multi-dimensional datasets: whole genome sequences, metabolomics, and cross-sectional and longitudinal cardiovascular phenotypes.
In Aim 1, we will aggregate and curate 75,000 deep (30X) whole genome sequences and cardiovascular phenotypes.
In Aim 2, we will discover genetic and non-genetic modifiers of LDL cholesterol and CHD risk in FH and evaluate their metabolomic consequences.
In Aim 3, we will develop a method incorporating genetics and longitudinal non- genetic exposures for CHD risk stratification among ~4,000 with FH mutations in the Million Veteran Program. In addition to the proposed Aims, this five-year proposal outlines a comprehensive strategy for the principal investigator's (PI's) scientific and professional development in academic cardiovascular medicine. The research strategy builds upon the PI's prior research experience and clinical training. In addition to an undergraduate degree in Molecular Biology and master's degree in Biomedical Informatics, he completed post- graduate medical training in Internal Medicine and Cardiovascular Medicine. He recently developed a new preventive/genetic cardiology clinic focusing on the evaluation and management of those with or a family history of premature CHD, including those with FH, at Massachusetts General Hospital (MGH). This proposal now focuses on expanding his scientific skills in human genetics and genomics into new domains: integrative genomics, statistical genetics, clinical informatics, and risk modeling. The career development goals will be at achieved through a multi-faceted approach involving mentorship, collaboration, didactic coursework, conferences, and scientific investigation. This work will take place in a unique training environment comprised of MGH and the Broad Institute. Successful completion of this career development award will result in improved fundamental understanding of the determinants of CHD, result in the PI's transition to an independent physician-scientist, and provide a solid foundation from which he will apply for R01-level funding.

Public Health Relevance

/ PUBLIC HEALTH RELEVANCE Cardiovascular disease, largely due to coronary heart disease (CHD), remains the leading cause of death in the United States and now worldwide despite current advances. Familial hypercholesterolemia is a relative common genetic disorder characterized by severe hypercholesterolemia and premature CHD but many carrying these mutations do not develop these consequences. This proposal seeks to define and characterize the factors modifying CHD risk among those with FH mutations; success has the potential to broadly identify new mechanisms of CHD and novel strategies for prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL140203-01
Application #
9431712
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Wang, Wayne C
Project Start
2017-12-07
Project End
2022-11-30
Budget Start
2017-12-07
Budget End
2018-11-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114