Genetic determinants of triglyceride-rich lipoproteins to disentangle CHD risk

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Project Abstract Cardiovascular disease, including coronary heart disease (CHD) and myocardial infarction (MI), is the leading cause of death in the United States. Genetic evidence has accumulated that triglyceride levels are a causal risk factor for CHD, beyond an individual's LDL-C. Triglyceride-rich lipoproteins (TRLs) contain cholesterol as well as triglycerides. An unanswered question is whether the cholesterol or the triglyceride content in TRLs drives the causal relationship of plasma TG levels on CHD risk. This application will leverage two longitudinal population-based cohorts: The Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). These cohorts represent over 7,000 individuals that have (1) nuclear magnetic resonance spectroscopy (NMR) lipoprotein profiling with estimates of cholesterol and triglyceride content of TRLs, (2) adjudicated CHD events and subclinical atherosclerosis measures over time, and (3) whole genome sequencing (WGS) data available through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. WGS provides an avenue for a complete evaluation of all genomic variation (both protein-coding and regulatory) across the allele frequency spectrum, while TRL subspecies provide fine-grained lipoprotein measurements. Aim 1 will harmonize the phenotypic and genotypic data at a central location and predict the joint effect of the cholesterol and triglyceride content of TRLs on CHD risk in FHS and MESA. Aim 2 will identify statistically independent variants associated with TRL subspecies and associate these with risk of CHD. An association analysis will be conducted using standardized lipoprotein profiles to identify genetic variants associated with each TRL subspecies. Measures of significance and annotation will identify the biologically plausible variants in genes (protein-coding) or in regulatory regions of the genome. 95% credible sets of SNPs will be determined to find candidate genes of interest or DNA regulatory regions. The effect of the identified genetic variants on each lipoprotein endo- phenotype will be compared. Finally, the genetic variation associated with lipoprotein subspecies will be associated with risk of CHD. This proposal will dive down a layer of depth in investigating the genetics of lipoproteins, and infer the role of the cholesterol and triglyceride content of the TRLs on risk of CHD. Identifying the genetic markers associated with TRLs subspecies will lead to a better understanding of the atherogenic mechanisms associated with triglyceride-rich lipoproteins in the population. Moreover, understanding the role of the triglyceride and cholesterol content that is driving the relationship with CHD is important to development of therapeutics through identifying better targets for therapy.