Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia (VARKIN)

September 21, 2023 updated by: Marja-Riitta Taskinen

Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia

The aims of the study are:

  1. To investigate if carriers of apolipoprotein (apo) CIII loss-of-function (LOF) mutations produce less apo-CIII that results in reduction of large very low-density lipoprotein (VLDL) particle secretion as compared to non-carriers of these variants and compare the results with carriers of apo-CIII gain-of-function (GOF) to elucidate the role of apo-CIII in hepatic lipid metabolism.
  2. To study if carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations produce less large VLDL particles to transport fat out of the liver as compared to non-carriers.
  3. To test whether the specific mutations in the apo-CIII, TM6SF2 and PNLPLA3 genes are reflected in changes of liver de novo lipogenesis (DNL), liver fat, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), plasma lipid and apolipoprotein kinetics and fasting concentrations in carriers of the TM6SF2 E167K and PNLPLA3 I148M mutations as compared to non-carriers.
  4. To study the effects of APOE, angiopoietin (ANGPTL3 and ANGPTL8) or endothelial lipase (LIPG) genotypes on liver fat metabolism, lipid and apolipoprotein metabolism and lipid phenotypes.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Enrolling by invitation

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Finland
      • Helsinki, Finland
        • RPU Clinical and Molecular Metabolism, Biomedicum
  • Sweden
      • Gothenburg, Sweden
        • Wallenberg Laboratory

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Ambulatory outpatients who are recruited from our previous study investigating familial dyslipidemia where exome sequency has been performed to explore genes involved in lipid metabolism (HUCH Ethics Committee, Department of Medicine: 108/1996, follow-up studies Dnro 170/E5/02, Drno 215/13/03/01/2009, Drno 144/13/03/01/2011 and HUCH Coordinating Ethics Committee Drno 184/13/03/00/2012, and Drno 183/13/03/00/2012). All subjects who have given oral consent that they can be informed about new studies focused on lipid metabolism will be contacted. To recruite the subjects we will use the invitation letter and follow up all the policy as stipulated in the Finnish biobank law (688/2012) (http//nationalbiobanks.fi/index.php./studies2/7-finrisk).

Description

Inclusion Criteria:

  • persons who have provided written consent
  • apo-CIII loss-of-function mutation (heterozygous) or apo-CIII gain-of-function mutations (heterozygous) or TM6SF2 E167K mutation (homozygous) or PNLPLA3 I148M or apoE or LIPG or ANGPTL3 or ANGPTL8 LOF and GOF variants. Control group without any of known risk variants in these genes.
  • Hemoglobin A1c < 6.5%
  • Body mass index between 18.5 and 40 kg/m²
  • Estimated glomerular filtration rate > 60 ml/min/1.73 m² at inclusion

Exclusion Criteria:

  • Patients with Type 1 and 2 diabetes, BMI > 40 kg/m2,
  • ApoE2/2 phenotype, thyrotropin concentration outside normal range,
  • Lipid-lowering drugs
  • Blood pressure >160 mmHg systolic and/or > 105 diastolic mmHg
  • Liver failure or abnormal liver function tests >3 x upper limit of normal
  • Intestinal disease
  • Pregnancy, breastfeeding
  • Patients with volume depletion

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
ApoC-III LOF
Carriers of apo-CIII loss-of-function mutation
Diagnostic test: Lipoprotein kinetics
Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.
Other Names:
  • Measurement of de novo lipogenesis
  • Measurement of lipolytic activity
  • Measurement of liver fat
ApoC-III GOF
Carriers of apo-CIII gain-of-function mutation
Diagnostic test: Lipoprotein kinetics
Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.
Other Names:
  • Measurement of de novo lipogenesis
  • Measurement of lipolytic activity
  • Measurement of liver fat
TM6SF2-KK
Carriers of TM6SF2 E167K mutation
Diagnostic test: Lipoprotein kinetics
Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.
Other Names:
  • Measurement of de novo lipogenesis
  • Measurement of lipolytic activity
  • Measurement of liver fat
PNLPLA3-MM
Carriers of PNLPLA3 I148M mutation
Diagnostic test: Lipoprotein kinetics
Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.
Other Names:
  • Measurement of de novo lipogenesis
  • Measurement of lipolytic activity
  • Measurement of liver fat
Control
No ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation
Diagnostic test: Lipoprotein kinetics
Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.
Other Names:
  • Measurement of de novo lipogenesis
  • Measurement of lipolytic activity
  • Measurement of liver fat
ApoE variants
Carriers of E2/2, E3/3 or E4/4 mutation
Diagnostic test: Lipoprotein kinetics
Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.
Other Names:
  • Measurement of de novo lipogenesis
  • Measurement of lipolytic activity
  • Measurement of liver fat
LIPG
LIPG gene LOF or GOF variant carriers
Diagnostic test: Lipoprotein kinetics
Lipoprotein kinetic apply protocol that endogenously label proteins and fatty acids with stable isotope-labeled amino acid and glycerol tracers. De novo lipogenesis is measured after ingestion of deuterated water to measure newly formed fatty acids in VLDL. Liver fat is measured with magnetic resonance spectroscopy and lipolytic enzymes with heparin test.
Other Names:
  • Measurement of de novo lipogenesis
  • Measurement of lipolytic activity
  • Measurement of liver fat
ANGPTL3 or ANGPTL8
ANGPTL3 and ANGPTL8 gene LOF or GOF variant carriers

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Difference in the rate of production of VLDL Apo B
Time Frame: Baseline
Production rate, mg/day
Baseline
Difference in the rate of production of VLDL Triglycerides
Time Frame: Baseline
Production rate, mg/kg/day
Baseline
Difference in the rate of production of VLDL ApoC-III and apoE
Time Frame: Baseline
Production rate, mg/kg/day
Baseline
Difference in the Fractional Catabolic Rate of VLDL Apo B
Time Frame: Baseline
Rate of disappearance, pools/day
Baseline
Difference in the Fractional Catabolic Rate of VLDL Triglycerides
Time Frame: Baseline
Rate of disappearance, pools/day
Baseline
Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE
Time Frame: Baseline
Rate of disappearance, pools/day
Baseline
Difference in de novo lipogenesis
Time Frame: Baseline
Measure of newly synthesized triglycerides in VLDL, μmol/l
Baseline
Difference in liver fat
Time Frame: Baseline
Percentage of liver fat measured with magnetic resonance spectroscopy
Baseline
Difference in atherogenic dyslipidemia
Time Frame: Baseline
Remnant lipoproteins and lipoprotein fraction composition, mg/L
Baseline
Difference in insulin resistance
Time Frame: Baseline
Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
Baseline
Difference in apoprotein A concentration
Time Frame: Baseline
ApoA, mg/dl
Baseline
Difference in apoprotein B concentration
Time Frame: Baseline
ApoB, mg/dl
Baseline
Difference in apoprotein C concentration
Time Frame: Baseline
ApoC, mg/dl
Baseline
Difference in apoprotein E concentration
Time Frame: Baseline
ApoE, mg/dl
Baseline
Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B
Time Frame: Baseline
Rate of turnover, pools/day
Baseline
Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B
Time Frame: Baseline
Rate of turnover, pools/day
Baseline
Lipolytic activity
Time Frame: Baseline
Measured lipoprotein lipase activity, mU/ml
Baseline
Hepatic lipase activity
Time Frame: Baseline
Measured hepatic lipase activity, mU/ml
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Marja-Riitta Taskinen

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Göteborg University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2019

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2024

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 19, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 20, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 24, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 22, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 21, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HUS/53/2017

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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