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

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ClinicalTrials.gov Identifier: NCT04061018
Recruitment Status : Enrolling by invitation
First Posted : August 19, 2019
Last Update Posted : August 19, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of Texas Southwestern Medical Center

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.

Condition or disease
Lipid Metabolism Disorders

Detailed Description:

The mechanisms that underlie variation in cholesterol efflux are unknown. There is a critical need to identify factors that regulate cholesterol efflux to effectively advance the clinical development of cholesterol efflux as both a risk prediction marker and as a target of therapy. The investigator's long-term goal is to determine whether modulating cholesterol efflux prevents or reverses cardiovascular disease. The overall objective of this study is to systematically create a family pedigree and biobank repository of blood and DNA from participants from the Dallas Heart Study with extreme low or high cholesterol efflux, with the specific aims of : 1) determining the heritability of and genomic factors associated with cholesterol efflux, and 2) identifying the protein and lipid signature of extreme low and high cholesterol efflux in a sex- and ethnicity-specific manner. The investigator's central hypothesis is that a combination of genetic variation in lipid transporters as well as proteins and lipids will be most strongly correlated with variation in efflux.

DHS probands and their relatives (parents, siblings, adult children, grandparents, aunts/uncles, cousins) with extreme low or high cholesterol efflux will be recruited to establish a prospective family pedigree cohort and understand the heritability of extreme cholesterol efflux. Investigators will collect the following information from all participants: demographics, health history, lifestyle measures, and medications. Blood will be collected on-site by venipuncture and plasma, serum, and cells will be stored at -80o Celsius. All efflux measurements will be completed in the investigator's laboratory.


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Study Type : Observational
Estimated Enrollment : 180 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: The Genetic, Protein, and Lipid Basis of Variation in Cholesterol Efflux
Actual Study Start Date : December 1, 2017
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2022

Resource links provided by the National Library of Medicine


Group/Cohort
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



Primary Outcome Measures :
  1. Contribution of genetic factors to variability in cholesterol efflux [ Time Frame: Anticipated completion date - November 2022 ]
    The expected outcome is establishing the degree of heritability of the extreme low or high cholesterol efflux phenotype, specific for sex and ethnicity and the contribution of common and rare genetic variants to cholesterol efflux. This will establish for the first time to what degree inherited verses environmental factors associate with variation in cholesterol efflux.

  2. Circulating metabolites and proteins linked to variation cholesterol efflux [ Time Frame: Anticipated completion date - November 2022 ]
    The investigators will measure circulating metabolites and proteins and identify the most relevant to the high/low cholesterol efflux phenotype, offering the potential to focus future studies targeting metabolic regulators of efflux.


Biospecimen Retention:   Samples With DNA
Plasma, Serum, DNA


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 89 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04061018


Locations
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United States, Texas
UT Southwestern Medical Center
Dallas, Texas, United States, 75390
Sponsors and Collaborators
University of Texas Southwestern Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Anand Rohatgi, MD UT Southwetsern Medical Center

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Responsible Party: University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT04061018     History of Changes
Other Study ID Numbers: STU042016-020
1R01HL136724-01A1 ( U.S. NIH Grant/Contract )
First Posted: August 19, 2019    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Texas Southwestern Medical Center:
HDL
Atherosclerotic Cardiovascular Disease
Cholesterol efflux
Additional relevant MeSH terms:
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Metabolic Diseases
Lipid Metabolism Disorders