Molecular Investigation of Genetic Factors in CArDiovascular Diseases Using an BIOresource of Healthy Volunteers

Summary

The risk of cardiovascular disease is determined by the complex interplay between an individual's genetic make-up, lifestyle, and the environment. We are investigating three potential genetic risk factors in this observational, cross-sectional, epidemiology pilot study to investigate if and how functional variants identified in large-scale genome wide association studies can explain a predisposition to cardiovascular disease. By determining the molecular mechanisms that are regulated at the EDNRA, PNPLA3 and PROCR CVD risk loci, we hope to translate findings from this study into the clinical setting for better diagnosis, prevention and treatment for patients suffering with cardiovascular disease. Volunteers will enter into one of the study's three arms based on their genotype: EDNRA locus (Arm 1), PNPLA3 locus (Arm 2), or PROCR locus (Arm 3).

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.

Conditions

• Cardiovascular Diseases

Interventions

OTHER

Eligibility and lifestyle restrictions check.

Eligibility will be assessed at each study visit and participants will be informed in advance of their visit.

OTHER

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.

OTHER

Anthropometric measurements: height, weight, and body fat

Height measured by stadiometer. Weight and body fat measured by Tanita scale bioelectrical impedance analysis.

OTHER

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.

OTHER

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.

OTHER

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.

OTHER

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.

OTHER

Blood EPCR function (PROCR)

Blood sample taken will be analysed via ELISA and FACS.

OTHER

Blood platelet coagulation and function (PROCR)

Blood sample taken will be analysed using a Platelet coagulation and function assay.

OTHER

Blood endothelial permeability (PROCR)

Blood sample will be analysed in vitro using a permeability assay kit.

OTHER

Blood leukocyte-endothelium adhesion (PROCR)

Blood sample will be analysed in vitro using a leukocyte-endothelium adhesion assay.

OTHER

Baseline Venepuncture (PNPLA3, Visit 1)

Up to 25ml Blood will be taken.

OTHER

Deuterium water - Loading dose 1 (PNPLA3, Visit 1)

Loading dose of 3 g/kg body water.

OTHER

Deuterium water - Loading dose 2 (PNPLA3, Visit 1)

Loading dose of 3 g/kg body water.

OTHER

Energy-balanced dinner (PNPLA3, Visit 1)

Provided following baseline bloods and loading dose 1.

OTHER

Fasting venepuncture (PNPLA3, Visit 2)

Up to 25ml Blood will be taken.

OTHER

Deuterium water - Maintenance dose (PNPLA3, Visit 2)

every hour, maintenance dose 0.04 g/kg body water

OTHER

Consumption of high carbohydrate meal (PNPLA3, Visit 2)

Provided following fasting blood sample.

OTHER

Postprandial Venepuncture (PNPLA3, Visit 2)

Up to 25ml Blood will be taken.

OTHER

Venepuncture (PROCR)

Up to 50ml Blood will be taken.

Sponsors & Collaborators

• University of Cambridge

  collaborator OTHER

• Cambridge University Hospitals NHS Foundation Trust

  lead OTHER

Principal Investigators

• Dirk Paul, PhD · University of Cambridge

Eligibility

Min Age

18 Years

Max Age

50 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2017-08-14

Primary Completion

2023-06-06

Completion

2023-06-06

Countries

• United Kingdom

Study Locations