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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01HL136724-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
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| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Anand Rohatgi, MD | UT Southwetsern Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UT Southwestern Medical Center | Dallas | Texas | 75390 | United States |
Though both Dallas Heart Study (DHS) patients with High/ Low Cholesterol Efflux and their family members were both enrolled in this study, the study population only included random set of 57 subjects from DHS that were below 10th or above 90th percentile of cholesterol efflux distribution. Though 29 family members were enrolled, they were not assigned to any of the below Arms/ Groups and didn't start on this study and therefore no data was collected on them.
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| ID | Title | Description |
|---|---|---|
| FG000 | High Cholesterol Efflux | Dallas Heart Study participants who are above the sex and ethnicity specific 90th % of cholesterol efflux |
| FG001 | Low Cholesterol Efflux | Dallas Heart Study participants who are below the sex and ethnicity specific 10th % of cholesterol efflux |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | High Cholesterol Efflux | Dallas Heart Study participants who are above the sex and ethnicity specific 90th % of cholesterol efflux |
| BG001 | Low Cholesterol Efflux | Dallas Heart Study participants who are below the sex and ethnicity specific 10th % of cholesterol efflux |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Posted | Median | Inter-Quartile Range | Ratio | Baseline |
|
24 hours from baseline visit
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | High Cholesterol Efflux | Dallas Heart Study participants who are above the sex and ethnicity specific 90th % of cholesterol efflux |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Anand Rohatgi | UTexasSouthwestern | 214/645-7531 | anand.rohatgi@utsouthwestern.edu |
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 21, 2021 | Oct 1, 2025 | Prot_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Oct 7, 2020 | Oct 1, 2025 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D052439 | Lipid Metabolism Disorders |
| D050197 | Atherosclerosis |
| ID | Term |
|---|---|
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
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Plasma, Serum, DNA
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Number of Participants with Hypercholesterolemia | Count of Participants | Participants |
|
| Number of Participants with Diabetes | Count of Participants | Participants |
|
| Number of Participants with Heart Disease | Count of Participants | Participants |
|
| Number of Participants with Hypertension | Count of Participants | Participants |
|
| Number of Participants Menopausal | Count of Participants | Participants |
|
| Number of Participants who are Current Smokers | Count of Participants | Participants |
|
| Number of Participants who drink Alcohol | 1 or more drinks a day | Count of Participants | Participants |
|
| Number of Participants who take Blood pressure medication | Count of Participants | Participants |
|
| Number of Participants who take Glucose medication | Count of Participants | Participants |
|
| Number of Participants who take Lipid medication | Count of Participants | Participants |
|
| OG001 | Low Cholesterol Efflux | Dallas Heart Study participants who are below the sex and ethnicity specific 10th % of cholesterol efflux |
|
|
| Primary | 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. | Posted | Median | Inter-Quartile Range | mmol/L | Baseline |
|
|
|
| Primary | 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. | Posted | Median | Inter-Quartile Range | umol/L | Baseline |
|
|
|
| Primary | 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. | Posted | Median | Inter-Quartile Range | G/L | Baseline |
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 0 |
| 30 |
| EG001 | Low Cholesterol Efflux | Dallas Heart Study participants who are below the sex and ethnicity specific 10th % of cholesterol efflux | 0 | 27 | 0 | 27 | 0 | 27 |
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| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Hemoglobin |
|