Molecular Investigation of Genetic Factors in CArDiovascular Diseases Using an BIOresource of Healthy Volunteers
NCT ID: NCT03038750
Last Updated: 2024-02-02
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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TERMINATED
74 participants
OBSERVATIONAL
2017-08-14
2023-06-06
Brief Summary
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Members of the Cambridge Bioresource who match for the target alleles will be invited to participate and will enter into one of the three study arms. All study assessment visits will take place at Addenbrooke's Hospital in collaboration with the University of Cambridge.
Volunteers will participate in the study for a maximum of 12 months and depending on study arm they are assigned to, they will complete procedures including a medical, demographic and lifestyle factors questionnaire; height, weight and body fat assessments; in addition to blood pressure/heart rate measurements. Minimally invasive procedures including forearm blood flow and venepuncture will be performed to assess the primary objectives of the study.
The hypothesis for arm 1 is that the genetic variant we are investigating at the EDNRA gene locus alters the function of the endothelin receptor A leading to an increased risk of coronary artery disease and large artery stroke.
For study arm 2, we hypothesize that the genetic variant we are investigating in PNPLA3 will increase the risk of Non-alcoholic fatty liver disease but reduce the risk of Coronary Heart Disease.
For study arm 3, we hypothesize that the genetic variant we are investigating in the PROCR locus triggers molecular events that potentially increase the risk of Venous Thrombosis/Venous Thromboembolism nut reducing blood pressure. Furthermore we aim to investigate the anti-inflammatory effects to see if there is an effect on explaining reduced risk of CHD.
This study is funded from the BHF Cambridge Center of Excellence and the Wellcome Trust Institutional Strategic Support Fund.
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Detailed Description
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Conditions
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Study Design
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COHORT
CROSS_SECTIONAL
Study Groups
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EDNRA Sub-study
Study population will be split into two groups defined by the allele of EDNRA the participant possesses:
Participants Homozygous for the A-allele of EDNRA, are assigned to the 'case' group.
Participants that are Homozygous for the G-allele will be assigned to the 'control' group.
20 participants will be recruited to each group, 40 in total.
Eligibility and lifestyle restrictions check.
Eligibility will be assessed at each study visit and participants will be informed in advance of their visit.
Medical history, demographic and lifestyle factors
Medical History, participants demographics and lifestyle factors will be assessed by the participant completion of the medical history and ethnicity questionnaires.
Anthropometric measurements: height, weight, and body fat
Height measured by stadiometer. Weight and body fat measured by Tanita scale bioelectrical impedance analysis.
Blood pressure and heart rate
Parameters will be measured using a validated, automated device while seated and again after 3-5 min standing. All measurements will be done in triplicate.
Forearm blood flow: Visit 1 (EDNRA)
Intra-arterial infusion of Phenylephrine at doses of 0.75, 2.5, and 7.5 μg/min for 6 min each (18 min in total). FBF measured in the last 3 minutes. There will be a 30 minute washout with saline followed by Endothelin-1 infusion of at a dose of 5 pmol/min for 90 min.
Forearm blood flow: Visit 2 (EDNRA)
Intra-arterial infusion of Sodium nitroprusside infusion at doses of 1, 3, and 10 μg/min for 6 min each (18 min in total). FBF measured in the last 3 minutes. There will be a 20 minute washout with saline followed by infusion of BQ-123 at a dose of 10 nmol/min for 90 min.
PNPLA3 Sub-study
Study population will be split into two groups defined by the allele of PNPLA3 the participant possesses:
Participants Homozygous for the G-allele of PNPLA3, are assigned to the 'case' group.
Participants that are Homozygous for the C-allele of PNPLA3 will be assigned to the 'control' group.
60 participants will be recruited to each group, 120 in total.
Eligibility and lifestyle restrictions check.
Eligibility will be assessed at each study visit and participants will be informed in advance of their visit.
Medical history, demographic and lifestyle factors
Medical History, participants demographics and lifestyle factors will be assessed by the participant completion of the medical history and ethnicity questionnaires.
Anthropometric measurements: height, weight, and body fat
Height measured by stadiometer. Weight and body fat measured by Tanita scale bioelectrical impedance analysis.
Blood pressure and heart rate
Parameters will be measured using a validated, automated device while seated and again after 3-5 min standing. All measurements will be done in triplicate.
Blood biochemistry (PNPLA3)
25ml blood will be taken from the participant in a glucose fasting state. Following a high carbohydrate meal, a second 25ml blood sample will be taken. Clinical Biochemistry tests and detailed lipid analysis will be performed.
Baseline Venepuncture (PNPLA3, Visit 1)
Up to 25ml Blood will be taken.
Deuterium water - Loading dose 1 (PNPLA3, Visit 1)
Loading dose of 3 g/kg body water.
Deuterium water - Loading dose 2 (PNPLA3, Visit 1)
Loading dose of 3 g/kg body water.
Energy-balanced dinner (PNPLA3, Visit 1)
Provided following baseline bloods and loading dose 1.
Fasting venepuncture (PNPLA3, Visit 2)
Up to 25ml Blood will be taken.
Deuterium water - Maintenance dose (PNPLA3, Visit 2)
every hour, maintenance dose 0.04 g/kg body water
Consumption of high carbohydrate meal (PNPLA3, Visit 2)
Provided following fasting blood sample.
Postprandial Venepuncture (PNPLA3, Visit 2)
Up to 25ml Blood will be taken.
PROCR Sub-study
Study population will be split into two groups defined by the allele of PROCR the participant possesses:
Participants Homozygous for the G-allele of PROCR, are assigned to the 'case' group.
Participants that are Homozygous for the A-allele of PROCR will be assigned to the 'control' group.
30 participants will be recruited to each group, 60 in total.
Eligibility and lifestyle restrictions check.
Eligibility will be assessed at each study visit and participants will be informed in advance of their visit.
Medical history, demographic and lifestyle factors
Medical History, participants demographics and lifestyle factors will be assessed by the participant completion of the medical history and ethnicity questionnaires.
Anthropometric measurements: height, weight, and body fat
Height measured by stadiometer. Weight and body fat measured by Tanita scale bioelectrical impedance analysis.
Blood pressure and heart rate
Parameters will be measured using a validated, automated device while seated and again after 3-5 min standing. All measurements will be done in triplicate.
Blood EPCR function (PROCR)
Blood sample taken will be analysed via ELISA and FACS.
Blood platelet coagulation and function (PROCR)
Blood sample taken will be analysed using a Platelet coagulation and function assay.
Blood endothelial permeability (PROCR)
Blood sample will be analysed in vitro using a permeability assay kit.
Blood leukocyte-endothelium adhesion (PROCR)
Blood sample will be analysed in vitro using a leukocyte-endothelium adhesion assay.
Venepuncture (PROCR)
Up to 50ml Blood will be taken.
Interventions
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Eligibility and lifestyle restrictions check.
Eligibility will be assessed at each study visit and participants will be informed in advance of their visit.
Medical history, demographic and lifestyle factors
Medical History, participants demographics and lifestyle factors will be assessed by the participant completion of the medical history and ethnicity questionnaires.
Anthropometric measurements: height, weight, and body fat
Height measured by stadiometer. Weight and body fat measured by Tanita scale bioelectrical impedance analysis.
Blood pressure and heart rate
Parameters will be measured using a validated, automated device while seated and again after 3-5 min standing. All measurements will be done in triplicate.
Forearm blood flow: Visit 1 (EDNRA)
Intra-arterial infusion of Phenylephrine at doses of 0.75, 2.5, and 7.5 μg/min for 6 min each (18 min in total). FBF measured in the last 3 minutes. There will be a 30 minute washout with saline followed by Endothelin-1 infusion of at a dose of 5 pmol/min for 90 min.
Forearm blood flow: Visit 2 (EDNRA)
Intra-arterial infusion of Sodium nitroprusside infusion at doses of 1, 3, and 10 μg/min for 6 min each (18 min in total). FBF measured in the last 3 minutes. There will be a 20 minute washout with saline followed by infusion of BQ-123 at a dose of 10 nmol/min for 90 min.
Blood biochemistry (PNPLA3)
25ml blood will be taken from the participant in a glucose fasting state. Following a high carbohydrate meal, a second 25ml blood sample will be taken. Clinical Biochemistry tests and detailed lipid analysis will be performed.
Blood EPCR function (PROCR)
Blood sample taken will be analysed via ELISA and FACS.
Blood platelet coagulation and function (PROCR)
Blood sample taken will be analysed using a Platelet coagulation and function assay.
Blood endothelial permeability (PROCR)
Blood sample will be analysed in vitro using a permeability assay kit.
Blood leukocyte-endothelium adhesion (PROCR)
Blood sample will be analysed in vitro using a leukocyte-endothelium adhesion assay.
Baseline Venepuncture (PNPLA3, Visit 1)
Up to 25ml Blood will be taken.
Deuterium water - Loading dose 1 (PNPLA3, Visit 1)
Loading dose of 3 g/kg body water.
Deuterium water - Loading dose 2 (PNPLA3, Visit 1)
Loading dose of 3 g/kg body water.
Energy-balanced dinner (PNPLA3, Visit 1)
Provided following baseline bloods and loading dose 1.
Fasting venepuncture (PNPLA3, Visit 2)
Up to 25ml Blood will be taken.
Deuterium water - Maintenance dose (PNPLA3, Visit 2)
every hour, maintenance dose 0.04 g/kg body water
Consumption of high carbohydrate meal (PNPLA3, Visit 2)
Provided following fasting blood sample.
Postprandial Venepuncture (PNPLA3, Visit 2)
Up to 25ml Blood will be taken.
Venepuncture (PROCR)
Up to 50ml Blood will be taken.
Eligibility Criteria
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Inclusion Criteria
* Arm 1: The A-allele of rs6841581, they are assigned to the 'case' group. If they are homozygous for the G-allele, they are assigned to the 'control' group
* Arm 2: The G-allele of rs738409, they are assigned to the 'case' group. If they are homozygous for the C-allele, they are assigned to the 'control' group
* Arm 3: The G-allele of rs867186, they are assigned to the 'case' group. If they are homozygous for the A-allele, they are assigned to the 'control' group
* Volunteers are aged between 18-50 years old
* Volunteers have a BMI:
* Arm 1: Between18.5-29.9
* Arm 2: Between 25.0-39.9
* Arm 3: Between 18.5-29.9
* Volunteers are willing not to consume products containing alcohol or caffeine 12 hours prior to procedures. Additionally, volunteers must agree to fast before procedures for:
* Arm 1: At least 4 hours
* Arm 2: At least 8 hours (for visit 2 only)
* Arm 3: At least 4 hours
* Have given written informed consent to participate
Exclusion Criteria
* Biological first-degree relatives (parents, brothers, sisters or children) who are or have suffered from one of the conditions described above
* Current smokers. Ex-smokers are suitable if they stopped smoking \>10 years ago
* Volunteers with a diagnosis of hypertension, or history of consistently high blood pressure readings, \>140/90 mmHg
* Volunteers with a diagnosis of hypercholesterolemia, or history of consistently high cholesterol levels, e.g. total cholesterol level \>6 mmol/l
* Volunteers have ≥3 alcoholic drinks per day
18 Years
50 Years
ALL
Yes
Sponsors
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University of Cambridge
OTHER
Cambridge University Hospitals NHS Foundation Trust
OTHER
Responsible Party
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Dirk Paul
Principal Investigator
Principal Investigators
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Dirk Paul, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Cambridge
Locations
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Department of Public Health and Primary Care
Cambridge, , United Kingdom
Countries
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Other Identifiers
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CADBIO
Identifier Type: -
Identifier Source: org_study_id
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