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Enrolling by Invitation

NCT Number: NCT04209816

Genetic Pathways Leading to 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.

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Key information

Conditions

Non-alcoholic Fatty Liver Atherogenic Dyslipidemia Digestive System Diseases Fatty Liver Glucose Metabolism Disorders Hyperinsulinism Insulin Resistance Liver Diseases Metabolic Diseases Non-alcoholic Fatty Liver Disease Nutritional and Metabolic Diseases

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Observational

Primary location

RPU Clinical and Molecular Metabolism, Biomedicum, Helsinki, Finland

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Lipoprotein kinetics

Diagnostic Test

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

Primary outcomes

  1. Difference in the rate of production of VLDL Apo B

    Time frame: Baseline

    Production rate, mg/day

  2. Difference in the rate of production of VLDL Triglycerides

    Time frame: Baseline

    Production rate, mg/kg/day

  3. Difference in the rate of production of VLDL ApoC-III and apoE

    Time frame: Baseline

    Production rate, mg/kg/day

  4. Difference in the Fractional Catabolic Rate of VLDL Apo B

    Time frame: Baseline

    Rate of disappearance, pools/day

  5. Difference in the Fractional Catabolic Rate of VLDL Triglycerides

    Time frame: Baseline

    Rate of disappearance, pools/day

  6. Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE

    Time frame: Baseline

    Rate of disappearance, pools/day

  7. Difference in de novo lipogenesis

    Time frame: Baseline

    Measure of newly synthesized triglycerides in VLDL, μmol/l

  8. Difference in liver fat

    Time frame: Baseline

    Percentage of liver fat measured with magnetic resonance spectroscopy

  9. Difference in atherogenic dyslipidemia

    Time frame: Baseline

    Remnant lipoproteins and lipoprotein fraction composition, mg/L

  10. Difference in insulin resistance

    Time frame: Baseline

    Calculated Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

  11. Difference in apoprotein A concentration

    Time frame: Baseline

    ApoA, mg/dl

  12. Difference in apoprotein B concentration

    Time frame: Baseline

    ApoB, mg/dl

  13. Difference in apoprotein C concentration

    Time frame: Baseline

    ApoC, mg/dl

  14. Difference in apoprotein E concentration

    Time frame: Baseline

    ApoE, mg/dl

  15. Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B

    Time frame: Baseline

    Rate of turnover, pools/day

  16. Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B

    Time frame: Baseline

    Rate of turnover, pools/day

  17. Lipolytic activity

    Time frame: Baseline

    Measured lipoprotein lipase activity, mU/ml

  18. Hepatic lipase activity

    Time frame: Baseline

    Measured hepatic lipase activity, mU/ml

Sponsors and collaborators

Lead sponsor

Marja-Riitta Taskinen

Other

Collaborators

  • Göteborg University

Registry information

Official study title

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

Acronym: VARKIN

Important dates

Study start
2019
Primary completion
2024
Study completion
2028
First posted
Dec 24, 2019
Registry last updated
Sep 22, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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