Clinical trial NCT04209816: Genetic Pathways Leading to Fatty Liver and Atherogenic Dyslipidemia
Official title: Genetic Regulation of Lipid Pathways Contributing to Non-alcoholic Fatty Liver and Atherogenic Dyslipidemia
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Non-alcoholic Fatty Liver
Atherogenic Dyslipidemia
Insulin Resistance
Keywords: Non-alcoholic Fatty Liver
Apoproteins
Genetic variants
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: Göteborg University
First posted: 2019-12-24
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
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).

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.


Eligibility 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

Primary outcomes:
measure: Difference in the rate of production of VLDL Apo B
timeFrame: Baseline
measure: Difference in the rate of production of VLDL Triglycerides
timeFrame: Baseline
measure: Difference in the rate of production of VLDL ApoC-III and apoE
timeFrame: Baseline
measure: Difference in the Fractional Catabolic Rate of VLDL Apo B
timeFrame: Baseline
measure: Difference in the Fractional Catabolic Rate of VLDL Triglycerides
timeFrame: Baseline
measure: Difference in the Fractional Catabolic Rate of VLDL ApoC-III and apoE
timeFrame: Baseline
measure: Difference in de novo lipogenesis
timeFrame: Baseline
measure: Difference in liver fat
timeFrame: Baseline
measure: Difference in atherogenic dyslipidemia
timeFrame: Baseline
measure: Difference in insulin resistance
timeFrame: Baseline
measure: Difference in apoprotein A concentration
timeFrame: Baseline
measure: Difference in apoprotein B concentration
timeFrame: Baseline
measure: Difference in apoprotein C concentration
timeFrame: Baseline
measure: Difference in apoprotein E concentration
timeFrame: Baseline
measure: Difference in the rate of production and Fractional Catabolic Rate of intermediate-density Apo B
timeFrame: Baseline
measure: Difference in the rate of production and Fractional Catabolic Rate of low-density lipoprotein Apo B
timeFrame: Baseline
measure: Lipolytic activity
timeFrame: Baseline
measure: Hepatic lipase activity
timeFrame: Baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: RPU Clinical and Molecular Metabolism, Biomedicum
city: Gothenburg
country: Sweden
facility: Wallenberg Laboratory
Study officials:
References:
citation: 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.