Enrolling by invitationNCT04209816VARKINUpdated Sep 22, 2023

Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia

An observational study in Non-alcoholic Fatty Liver, Atherogenic Dyslipidemia and Insulin Resistance, sponsored by Marja-Riitta Taskinen. Enrolling by invitation at 2 sites in 2 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2023-09-22.

Sponsored by Marja-Riitta Taskinen · Observational

From the registry’s dates

Primary completion was expected by Jun 2024, 2 years 4 months ago, but the record still lists the study as enrolling by invitation.

Study type: Observational
Model: Case-control
Time perspective: Cross-sectional
Enrollment: 100
Ages: 18 Years to 70 Years
Sex: All

Study summary

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.

Conditions studied

Non-alcoholic Fatty Liver
Atherogenic Dyslipidemia
Insulin Resistance

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Keywords

Non-alcoholic Fatty Liver
Apoproteins
Genetic variants

In context

Fatty Liver

1,451 studies on the registry are indexed under Fatty Liver; 292 are open to participants now.

This study's planned enrollment of 100 is below the median of 140 across 397 observational studies indexed under Fatty Liver.

Browse Fatty Liver studies →

Lead sponsor

Marja-Riitta Taskinen is the lead sponsor of 3 studies on the registry; 1 is open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 70 Years
Sexes eligible: All
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).

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

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 design

Observational model: Case-control
Time perspective: Cross-sectional
Enrollment: 100 participants (estimated)
Patient registry: No
Biospecimen retention: Samples without dna

Groups and cohorts

ApoC-III LOF
Carriers of apo-CIII loss-of-function mutation
Diagnostic Test: Lipoprotein kinetics
ApoC-III GOF
Carriers of apo-CIII gain-of-function mutation
Diagnostic Test: Lipoprotein kinetics
TM6SF2-KK
Carriers of TM6SF2 E167K mutation
Diagnostic Test: Lipoprotein kinetics
PNLPLA3-MM
Carriers of PNLPLA3 I148M mutation
Diagnostic Test: Lipoprotein kinetics
Control
No ApoC-III, TM6SF2 E167K or PNLPLA3 I148M mutation
Diagnostic Test: Lipoprotein kinetics
ApoE variants
Carriers of E2/2, E3/3 or E4/4 mutation
Diagnostic Test: Lipoprotein kinetics
LIPG
LIPG gene LOF or GOF variant carriers
Diagnostic Test: Lipoprotein kinetics
ANGPTL3 or ANGPTL8
ANGPTL3 and ANGPTL8 gene LOF or GOF variant carriers

Interventions

Diagnostic testLipoprotein 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.
Also known as: Measurement of de novo lipogenesis, Measurement of lipolytic activity, Measurement of liver fat

What researchers measure

Primary outcomes

Difference in the rate of production of VLDL Apo B
Production rate, mg/day
Time frame: Baseline
Difference in the rate of production of VLDL Triglycerides
Production rate, mg/kg/day
Time frame: Baseline
Difference in the rate of production of VLDL ApoC-III and apoE
Production rate, mg/kg/day
Time frame: Baseline
Difference in the Fractional Catabolic Rate of VLDL Apo B
Rate of disappearance, pools/day
Time frame: Baseline
Difference in the Fractional Catabolic Rate of VLDL Triglycerides
Rate of disappearance, pools/day
Time frame: Baseline
Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE
Rate of disappearance, pools/day
Time frame: Baseline
Difference in de novo lipogenesis
Measure of newly synthesized triglycerides in VLDL, μmol/l
Time frame: Baseline
Difference in liver fat
Percentage of liver fat measured with magnetic resonance spectroscopy
Time frame: Baseline
Difference in atherogenic dyslipidemia
Remnant lipoproteins and lipoprotein fraction composition, mg/L
Time frame: Baseline
Difference in insulin resistance
Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
Time frame: Baseline
Difference in apoprotein A concentration
ApoA, mg/dl
Time frame: Baseline
Difference in apoprotein B concentration
ApoB, mg/dl
Time frame: Baseline
Difference in apoprotein C concentration
ApoC, mg/dl
Time frame: Baseline
Difference in apoprotein E concentration
ApoE, mg/dl
Time frame: Baseline
Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B
Rate of turnover, pools/day
Time frame: Baseline
Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B
Rate of turnover, pools/day
Time frame: Baseline
Lipolytic activity
Measured lipoprotein lipase activity, mU/ml
Time frame: Baseline
Hepatic lipase activity
Measured hepatic lipase activity, mU/ml
Time frame: Baseline

Study locations

2 sites

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

References and documents

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 ↗

Individual participant data

Plan to share: Undecided

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Sep 22, 2023, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT04209816
Lead sponsor: Marja-Riitta Taskinen
Collaborators: Göteborg University
Responsible party: Marja-Riitta Taskinen (Professor, Helsinki University Central Hospital) — Sponsor-investigator
First posted: Dec 24, 2019
Start date: Dec 1, 2019
Primary completion: Jun 2024 (estimated)
Completion: Dec 2028 (estimated)
Last update: Sep 22, 2023

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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