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

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ClinicalTrials.gov Identifier: NCT04209816
Recruitment Status : Enrolling by invitation
First Posted : December 24, 2019
Last Update Posted : December 24, 2019
Sponsor:
Collaborator:
Göteborg University
Information provided by (Responsible Party):
Marja-Riitta Taskinen, Helsinki University Central Hospital

Brief 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 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.

Condition or disease Intervention/treatment
Non-alcoholic Fatty Liver Atherogenic Dyslipidemia Insulin Resistance Diagnostic Test: Lipoprotein kinetics

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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia
Actual Study Start Date : December 1, 2019
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : December 2028


Group/Cohort Intervention/treatment
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



Primary Outcome Measures :
  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


Biospecimen Retention:   Samples Without DNA
Plasma and serum samples


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   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).
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04209816


Locations
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Finland
RPU Clinical and Molecular Metabolism, Biomedicum
Helsinki, Finland
Sweden
Wallenberg Laboratory
Gothenburg, Sweden
Sponsors and Collaborators
Marja-Riitta Taskinen
Göteborg University
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Responsible Party: Marja-Riitta Taskinen, Professor, Helsinki University Central Hospital
ClinicalTrials.gov Identifier: NCT04209816    
Other Study ID Numbers: HUS/53/2017
First Posted: December 24, 2019    Key Record Dates
Last Update Posted: December 24, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Marja-Riitta Taskinen, Helsinki University Central Hospital:
Non-alcoholic Fatty Liver
Apoproteins
Genetic variants
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Insulin Resistance
Dyslipidemias
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Liver Diseases
Digestive System Diseases
Lipid Metabolism Disorders