The Genetic, Protein, and Lipid Basis of Variation in Cholesterol Efflux

NCT04061018 | Completed Results

• 2 other identifiers: STU 042016-0201R01HL136724-01A1
• Study Type: observational
• Target: 86
• Locations: 1 country
• Sites: 1

Brief Summary

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. The investigators expect to identify genetic variants and sex- and ethnicity-specific combinations of proteins and lipids in participants with extreme low and high efflux that may lead to novel ways to modulate efflux. This proposal leverages a well-phenotyped population-based study to characterize the gene-protein-lipid signature of 1) extremes of cholesterol efflux in a sex- and ethnicity-specific manner. Successful completion of these aims will have immediate and direct impact on the use of cholesterol efflux as a clinically relevant biomarker of therapeutic benefit and are necessary for the clinical development of appropriate new targets for manipulation of the key atheroprotective function of cholesterol efflux to reduce ASCVD.

Conditions

Lipid Metabolism Disorders

Keywords

HDL; Atherosclerotic Cardiovascular Disease; Cholesterol efflux

Outcome Measures

Primary Outcomes (4)

• Cholesterol Efflux Capacity (CEC)

  Cholesterol efflux capacity (CEC) was determined by measuring the efflux of a fluorophore tagged cholesterol, BODIPY (Avanti polar lipids), from J774 murine macrophages (ATCC) to an appropriate acceptor. Efflux is calculated as a unitless measure by using the following formula: \[(µCi of 3H-cholesterol in media containing apoB-depleted subject plasma - µCi of 3H-cholesterol in plasma-free media) / (µCi of 3H-cholesterol in media containing apoB-depleted pooled control plasma-µCi of 3H-cholesterol in pooled control plasma-free media)\]. Cholesterol efflux capacity is inversely correlated with incidence of cardiovascular events (i.e. higher cholesterol efflux capacity is better for patients).

  Baseline

• Circulating Metabolite (Glucose) Linked to Variation Cholesterol Efflux

  The investigators will measure circulating metabolite (glucose) and identify the most relevant to the high/low cholesterol efflux phenotype, offering the potential to focus future studies targeting metabolic regulators of efflux.

  Baseline

• Circulating Metabolite (Creatinine) Linked to Variation Cholesterol Efflux

  The investigators will measure circulating metabolite (creatinine) and identify the most relevant to the high/low cholesterol efflux phenotype, offering the potential to focus future studies targeting metabolic regulators of efflux.

  Baseline

• Circulating Proteins Linked to Variation Cholesterol Efflux

  The investigators will measure circulating proteins (apolipoprotein A-I, Albumin, Hemoglobin) and identify the most relevant to the high/low cholesterol efflux phenotype, offering the potential to focus future studies targeting metabolic regulators of efflux.

  Baseline

Study Arms (2)

High Cholesterol Efflux

Dallas Heart Study participants who are above the sex and ethnicity specific 90th % of cholesterol efflux

Low Cholesterol Efflux

Dallas Heart Study participants who are below the sex and ethnicity specific 10th % of cholesterol efflux

Eligibility Criteria

• Age: 18 Years - 89 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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. https://www.utsouthwestern.edu/edumedia/edufiles/research/center\_translational\_medicine/dallas\_heart\_study/dhs-study-overview.pdf

You may qualify if:

• 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

You may not qualify if:

• HIV
• Cancer
• Autoimmune diseases
• Pregnancy

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• University of Texas Southwestern Medical Center: lead

Study Sites (1)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

Plasma, Serum, DNA

MeSH Terms

Conditions

Lipid Metabolism Disorders; Atherosclerosis

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Dr. Anand Rohatgi
• Organization: UTexasSouthwestern

anand.rohatgi@utsouthwestern.edu

214/645-7531

Study Officials

• Anand Rohatgi, MD

  UT Southwetsern Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: July 26, 2019
• First Posted: August 19, 2019
• Study Start: December 1, 2017
• Primary Completion: December 1, 2023
• Study Completion: May 31, 2025
• Last Updated: March 20, 2026
• Results First Posted: March 20, 2026

Record last verified: 2026-02

Locations

US (1)