Cholesterol efflux is a direct reflection of reverse cholesterol transport, a key atheroprotective pathway, and impaired efflux is associated with increased ASCVD risk. We established in the Dallas Heart Study that baseline differences in the anti-atherogenic process of cholesterol efflux are relevant to incident ASCVD risk in humans. Intriguingly, correlation with HDL composition was weak, suggesting that cholesterol efflux represents a novel lipid trait distinct from HDL. The mechanisms underlying variation in cholesterol efflux remain unknown. Our current efforts are focused on identifying the genetic and molecular factors that underlie variation in cholesterol efflux in two large, multi-ethnic population-based cohorts: DHS and MESA (supported by NHLBI R01). We use FPLC-profiling and other methods to further phenotype the efflux trait and focus on drivers of efflux in humans.
We are intimately interested in collaboration with other investigators and can serve as a core lab in measuring cholesterol efflux from human serum/plasma.
Extremes in HDL-C. Although high HDL-C levels are presumed to be protective from ASCVD, extreme elevations ≥ 90th% are associated with increased CV mortality. Although some of this association is confounded by environmental habits such as alcohol ingestion, the association persists despite adjustment for lifestyle factors. In addition, extreme elevations in HDL-C can represent dysfunctional HDL with impaired efflux and other functions and may also identify genetic mutations that confer increased ASCVD risk. Thus, we are keenly interested in identifying such individuals prospectively to investigate the molecular basis of dysfunctional HDL at such extreme elevations. We have initiated an extreme lipids repository at UT Southwestern to recruit those with extreme elevations in HDL-C for further deep lipid phenotyping and genotyping (supported by NHLBI K24). This repository will also allow genotyping and deep phenotyping of multiple lipid traits at both extreme high and low ranges.
We are interested in recruiting individuals with extreme HDL and other lipid levels for this repository.
Ongoing Projects
Extreme Lipids Repository
This is a prospective, observational study to establish a repository of samples from patients with extreme lipid phenotypes including but not limited to hyperlipidemia, dyslipidemia, hyperlipoproteinemia, extreme low/high HDL levels and deranged lipoprotein metabolism. The investigators plan to conduct sophisticated composition and functional analyses as well as genetic analysis to better understand the determinants of extreme lipid derangements.
Inclusion Criteria:
- adult patients (age 18 years or older) diagnosed with any lipid or metabolic disorder including hyperlipidemia,
- dyslipidemia, hyperlipoproteinemia, low HDL levels and deranged lipoprotein metabolism
Exclusion Criteria:
- Anyone under 18 years of age will be excluded from the study.
Status: Recruiting
Clinical Study Identifier: NCT04156997
The Genetic, Protein and Lipid Basis of Variation in Cholesterol Efflux
The rationale of this research is that deep phenotyping of individuals at the extremes of cholesterol efflux will identify key determinants of efflux that are potential novel therapeutic targets to prevent or reverse Atherosclerotic Cardiovascular Disease (ASCVD). The investigators propose to carry out the objective by studying participants at extreme low and high cholesterol efflux identified from the investigator's study in the population-based Dallas Heart Study by accomplishing the following aims: 1) determine the heritability of and genomic factors associated with cholesterol efflux by establishing a family pedigree of extreme low and high efflux and sequencing candidate genes involved in HDL metabolism; and 2) identify the protein and lipid signature of extreme low and high cholesterol efflux in a sex- and ethnicity-specific manner using mass spectroscopy and ELISA in FPLC-derived fractions.
Study Population
Participants from the Dallas Heart Study (DHS) with extreme low or high cholesterol efflux will be recruited in this study. DHS is a multi-ethnic, population based probability sample of Dallas County designed to define the social and the biological variables contributing to ethnic differences in cardiovascular health at the community level.
Inclusion Criteria:
- Dallas Heart Study (DHS) Participants who are above or below the sex- and ethnicity-specific 10th and 90th% of cholesterol efflux.
- Family members of the DHS participants are also eligible.
Exclusion Criteria:
- HIV
- Cancer
- Autoimmune diseases
- Pregnancy
Status: Active, not recruiting
Clinical Study Identifier: NCT04061018
The Effect of Exercise Training on HDL Function in Sedentary Adults
The goal of the proposed study is to confirm and expand our dose-response findings across multiple exercise doses, exercise modes, and HDL functions, as well as to comprehensively identify the biological, clinical, and molecular factors underlying exercise-induced changes in HDL function by leveraging existing samples and data (N=1224) from four large, completed NIH-funded clinical exercise trials:
- HERITAGE Family Study (N=731; 5 mos, same aerobic dose in healthy adults)
- STRRIDE AT/RT (N=144; 8 mos, aerobic, resistance, or combination training in overweight adults with mild dyslipidemia)
- STRRIDE-PD (N=175; 6 mos, 4 groups differing in aerobic exercise amount and/or intensity in adults with pre[1]diabetes)
- HART-D study (N=174; 9 mos, time-matched aerobic, resistance, or combination training in diabetics).
The Rohatgi Lab is a core lab for this project and measuring cholesterol efflux capacity in all the proposed cohorts.