Non-alcoholic Fatty LiverVARKINNCT04209816
Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia
An observational study of Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia, run by Marja-Riitta Taskinen at 2 sites in 2 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Non-alcoholic Fatty Liver, Atherogenic Dyslipidemia, Insulin Resistance
- What is being tested?
- Lipoprotein kinetics
- How many people
- 100 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 1 Dec 2019to Dec 2028
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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).
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
2 sites in 2 countries. Contact the study team or a site near you to ask about taking part.
2 sites in 2 countries
About this study
Official title: Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia
The aims of the study are:
- 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.
- 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.
- 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.
- 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.
- Being tested
- Lipoprotein kinetics
- Keywords
- Non-alcoholic Fatty Liver, Apoproteins, Genetic variants
- Medical subject headings
- Non-alcoholic Fatty Liver Disease, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lipoprotein kineticsDiagnostic test
Also called Measurement of de novo lipogenesis, Measurement of lipolytic activity, Measurement of liver fat
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.
| Study group | Role | What they receive |
|---|---|---|
| ApoC-III LOF | Carriers of apo-CIII loss-of-function mutation Receives: Diagnostic Test: Lipoprotein kinetics | |
| ApoC-III GOF | Carriers of apo-CIII gain-of-function mutation Receives: Diagnostic Test: Lipoprotein kinetics | |
| TM6SF2-KK | Carriers of TM6SF2 E167K mutation Receives: Diagnostic Test: Lipoprotein kinetics | |
| PNLPLA3-MM | Carriers of PNLPLA3 I148M mutation Receives: Diagnostic Test: Lipoprotein kinetics | |
| Control | No ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation Receives: Diagnostic Test: Lipoprotein kinetics | |
| ApoE variants | Carriers of E2/2, E3/3 or E4/4 mutation Receives: Diagnostic Test: Lipoprotein kinetics | |
| LIPG | LIPG gene LOF or GOF variant carriers Receives: Diagnostic Test: Lipoprotein kinetics | |
| ANGPTL3 or ANGPTL8 | ANGPTL3 and ANGPTL8 gene LOF or GOF variant carriers |
What is being measured
The primary outcome is the main question the study is designed to answer.
Difference in the rate of production of VLDL Apo B
Production rate, mg/day
Measured: Baseline
Difference in the rate of production of VLDL Triglycerides
Production rate, mg/kg/day
Measured: Baseline
Difference in the rate of production of VLDL ApoC-III and apoE
Production rate, mg/kg/day
Measured: Baseline
Difference in the Fractional Catabolic Rate of VLDL Apo B
Rate of disappearance, pools/day
Measured: Baseline
Difference in the Fractional Catabolic Rate of VLDL Triglycerides
Rate of disappearance, pools/day
Measured: Baseline
Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE
Rate of disappearance, pools/day
Measured: Baseline
Difference in de novo lipogenesis
Measure of newly synthesized triglycerides in VLDL, μmol/l
Measured: Baseline
Difference in liver fat
Percentage of liver fat measured with magnetic resonance spectroscopy
Measured: Baseline
Difference in atherogenic dyslipidemia
Remnant lipoproteins and lipoprotein fraction composition, mg/L
Measured: Baseline
Difference in insulin resistance
Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
Measured: Baseline
Difference in apoprotein A concentration
ApoA, mg/dl
Measured: Baseline
Difference in apoprotein B concentration
ApoB, mg/dl
Measured: Baseline
Difference in apoprotein C concentration
ApoC, mg/dl
Measured: Baseline
Difference in apoprotein E concentration
ApoE, mg/dl
Measured: Baseline
Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B
Rate of turnover, pools/day
Measured: Baseline
Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B
Rate of turnover, pools/day
Measured: Baseline
Lipolytic activity
Measured lipoprotein lipase activity, mU/ml
Measured: Baseline
Hepatic lipase activity
Measured hepatic lipase activity, mU/ml
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2019
- Study start1 Dec 2019
- Primary completionJun 2024 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Non-alcoholic Fatty LiverStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Marja-Riitta Taskinen
- Sponsor type
- University, hospital or other
- Collaborators
- Göteborg University
- Responsible party
- Sponsor-investigator, Marja-Riitta Taskinen, Helsinki University Central Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04209816
- Sponsor's protocol ID
- HUS/53/2017
- Acronym
- VARKIN
- Status last verified
- Sep 2023
- First submitted
- 19 Dec 2019
- Last updated
- 22 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Taskinen MR, Bjornson E, Matikainen N, Soderlund S, Ramo J, Ainola MM, Hakkarainen A, Sihlbom C, Thorsell A, Andersson L, Bergh PO, Henricsson M, Romeo S, Adiels M, Ripatti S, Laakso M, Packard CJ, Boren J. Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations. JCI Insight. 2022 Oct 10;7(19):e160607. doi: 10.1172/jci.insight.160607.
PubMed 36040803
Study at a glance
From the registry record, last updated by the sponsor on 22 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia
- ClinicalTrials.gov ID
- NCT04209816
- Acronym / sponsor ID
- VARKIN / HUS/53/2017
- Keywords
- Non-alcoholic Fatty Liver, Apoproteins, Genetic variants
- Study type
- Observational
- Recruitment status
- Enrolling by invitation
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Marja-Riitta TaskinenUniversity, hospital or other
- Collaborators
- Göteborg University
- Study start
- 1 Dec 2019 (actual)
- Primary completion
- Jun 2024 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 24 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aims of the study are:
- 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.
- 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.
- 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.
- 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 design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 8
| Arm | Type | Receives |
|---|---|---|
| ApoC-III LOF | – | Diagnostic Test: Lipoprotein kineticsCarriers of apo-CIII loss-of-function mutation |
| ApoC-III GOF | – | Diagnostic Test: Lipoprotein kineticsCarriers of apo-CIII gain-of-function mutation |
| TM6SF2-KK | – | Diagnostic Test: Lipoprotein kineticsCarriers of TM6SF2 E167K mutation |
| PNLPLA3-MM | – | Diagnostic Test: Lipoprotein kineticsCarriers of PNLPLA3 I148M mutation |
| Control | – | Diagnostic Test: Lipoprotein kineticsNo ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation |
| ApoE variants | – | Diagnostic Test: Lipoprotein kineticsCarriers of E2/2, E3/3 or E4/4 mutation |
| LIPG | – | Diagnostic Test: Lipoprotein kineticsLIPG gene LOF or GOF variant carriers |
| ANGPTL3 or ANGPTL8 | – | –ANGPTL3 and ANGPTL8 gene LOF or GOF variant carriers |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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).
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lipoprotein kineticsAlso: Measurement of de novo lipogenesis, Measurement of lipolytic activity, Measurement of liver fatLipoprotein 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. | Diagnostic test | ApoC-III GOF, ApoC-III LOF, ApoE variants, Control, LIPG, PNLPLA3-MM, TM6SF2-KK |
Primary outcome
Difference in the rate of production of VLDL Apo B
Time frame: Baseline
Production rate, mg/day
Difference in the rate of production of VLDL Triglycerides
Time frame: Baseline
Production rate, mg/kg/day
Difference in the rate of production of VLDL ApoC-III and apoE
Time frame: Baseline
Production rate, mg/kg/day
Difference in the Fractional Catabolic Rate of VLDL Apo B
Time frame: Baseline
Rate of disappearance, pools/day
Difference in the Fractional Catabolic Rate of VLDL Triglycerides
Time frame: Baseline
Rate of disappearance, pools/day
Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE
Time frame: Baseline
Rate of disappearance, pools/day
Difference in de novo lipogenesis
Time frame: Baseline
Measure of newly synthesized triglycerides in VLDL, μmol/l
Difference in liver fat
Time frame: Baseline
Percentage of liver fat measured with magnetic resonance spectroscopy
Difference in atherogenic dyslipidemia
Time frame: Baseline
Remnant lipoproteins and lipoprotein fraction composition, mg/L
Difference in insulin resistance
Time frame: Baseline
Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
Difference in apoprotein A concentration
Time frame: Baseline
ApoA, mg/dl
Difference in apoprotein B concentration
Time frame: Baseline
ApoB, mg/dl
Difference in apoprotein C concentration
Time frame: Baseline
ApoC, mg/dl
Difference in apoprotein E concentration
Time frame: Baseline
ApoE, mg/dl
Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B
Time frame: Baseline
Rate of turnover, pools/day
Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B
Time frame: Baseline
Rate of turnover, pools/day
Lipolytic activity
Time frame: Baseline
Measured lipoprotein lipase activity, mU/ml
Hepatic lipase activity
Time frame: Baseline
Measured hepatic lipase activity, mU/ml
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Sep 2023.
- Derived from this study: PubMed 36040803Taskinen MR, Bjornson E, Matikainen N, Soderlund S, Ramo J, Ainola MM, Hakkarainen A, Sihlbom C, Thorsell A, Andersson L, Bergh PO, Henricsson M, Romeo S, Adiels M, Ripatti S, Laakso M, Packard CJ, Boren J. Postprandial metabolism of apolipoproteins B48, B100, C-III, and E in humans with APOC3 loss-of-function mutations. JCI Insight. 2022 Oct 10;7(19):e160607. doi: 10.1172/jci.insight.160607.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia, run by Marja-Riitta Taskinen at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: enrolling by invitation, as of the sponsor's last update on 22 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Finland, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in the rate of production of VLDL Apo B (time frame: Baseline). The study lists 18 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04209816, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2023.