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HYPOCHOL : A Genetically-based Strategy to Identify New Targets in Cholesterol Metabolism (HYPOCHOL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02354079
Recruitment Status : Completed
First Posted : February 3, 2015
Last Update Posted : March 9, 2022
Information provided by (Responsible Party):
Nantes University Hospital

Brief Summary:
The aim of this study is to identify new targets in cholesterol metabolism thanks to a genetically-based strategy.

Condition or disease Intervention/treatment Phase
Hypobetalipoproteinemia Genetic: hypobetalipoproteinemia genetic and genotypic screening Not Applicable

Detailed Description:

The goal is to recruit 400 subjects: 200 adult subjects with familial hypobetalipoproteinemia (FHBL) (index cases) plus 200 additional related subjects in at least 10 large informative FHBL families, in which there is no known mutation in FHBL genes.

The patient care is modified: patient will have an Hospital Anxiety and Depression (HAD) questionnaire (focus on depressive syndrome), a food diary, and some additional blood analysis (including genetic analysis).

One of the main issue to recruit FHBL patients is the fact that they are asymptomatic and that FHBL is not identified as a serious illness by their general physicians.

Step-1. Excluding mutations in selected candidate genes As a first approach to screen candidate genes and exclude patients with known mutations, the investigators developed a custom design based on the Haloplex™ technology (Agilent® Technologies) to perform high-throughput sequencing of the coding regions of 10 genes, including those previously described in FHBL (apolipoprotein B (APOB), Proprotein convertase subtilisin/kexin type 9 (PCSK9)), Microsomal triglyceride transfer protein (MTP or ABL), chylomicron retention disease (CMRD), Secretion associated, Ras related GTPase (SARA2 gene), as well as 6 additional candidate genes in cholesterol metabolism (low density lipoprotein receptor (LDLR), Sortilin (SORT1), Inducible Degrader of the LDL receptor (IDOL), Cholesteryl ester transfer protein (CETP), Apolipoprotein E (ApoE) and Angiopoietin-like Protein 3 (ANGTPL3)). All the recruited index cases (n=200) will be genotyped to select only those without mutations in previously described genes, being approximately 50% of our index case cohort.

Step-2. Identification of informative families and exome sequencing In patients without identified mutations, the investigators will conduct a familial screening in order to identify other cases of FHBL among proband relatives. An analysis of fasting plasma lipid parameters (total cholesterol (TC), High density lipoprotein cholesterol (HDL-C), Low-Density Lipoproteins (LDL-C) and triglycerides (TG)) will be performed for each related. Affected subjects will be determined by a spontaneous LDL-C < 80 mg/dl and/or apoB < 50 mg/dl. In contrast, non-affected subjects will display LDL-C > 80 mg/dl and/or apoB > 50 mg/dl.

For large families, the investigators will then combine whole-exome sequencing and linkage analysis to identify any novel genetic variant likely explaining FHBL. Depending on family pedigree, whole-exome sequencing (WES) will be performed on 2 to 5 patients per family. All relatives will be genotyped for linkage analysis.

In parallel to this genetic approach, a regional epidemiological analysis will be performed to identify some geographical clusters with a high prevalence of the disease, as developed in the project named VaCaRMe (for Vascular and Cardiac, Respiratory and Metabolic overcome diseases)

An additional aim, based on an exhaustive phenotyping of FHBL patients, is to investigate the safety of very low LDL-C and to perform some genotype-phenotype correlations in patients with FHBL population."

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 435 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: HYPOCHOL : A Genetically-based Strategy to Identify New Targets in Cholesterol Metabolism
Actual Study Start Date : January 7, 2016
Actual Primary Completion Date : January 7, 2022
Actual Study Completion Date : January 7, 2022

Arm Intervention/treatment
genetic analysis Genetic: hypobetalipoproteinemia genetic and genotypic screening

Primary Outcome Measures :
  1. type and number of genetic abnormalities leading to FHBL [ Time Frame: ten years ]
    To identify new gene involved in FHBL and determine genetic cause of FHBL (Patients with FHBL and their relatives will be recruited to establish familial forms of FHBL in large informative families with no mutations in known classical FHBL genes. This will allow perform genetic analysis using new approaches to genetic broadband (exome sequencing analysis + linkage analysis). This approach will allow specify which chromosomal regions are shared only by affected individuals, and identify new candidate genes).

Other Outcome Measures:
  1. number of phenotypes associated to genotype of FHBL and very low LDL-C [ Time Frame: ten years ]
    To determine number of phenotypes associated to genotype of FHBL and very low LDL-C. (Liver steatosis, Glucose homeostasis, Cancer, Depression scores, Cardiovascular diseases).

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:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • For index cases without family screening:

    o Patient with HBL: fasting LDL-C ≤ 50 mg/dl.

  • For familial affected cases:

    • Relative with HBL: fasting LDL-C ≤ 80 mg/dl and/or Apo B ≤ 50 mg/dl and at least one related family case suffering from HBL.

All subjects, including familial non-affected cases, must give written consent (dated and signed) to participate at the constitution of biobank (including DNA samples and urine samples).

Exclusion Criteria:

  • Use of lipid-lowering drugs (statins, fibrates, ezetimibe, bile-acid sequestering resin) or nutraceuticals known to affect lipids (red yeast rice, margarine and dairy with plant sterol)
  • Patient screened within an extreme metabolic disturbance (emergency situations, sepsis, hospitalization in intensive care unit)
  • Patients with hyperthyroidism, severe liver failure, end stage chronic kidney disease, serious pancreatic failure, anemia related to thalassemia or sickle cell disease, strict vegan diet or malnutrition
  • Refusal of the patient or his legal representative to participate in the study"

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 identifier (NCT number): NCT02354079

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CHU de Nantes
Nantes, France, 44093
Sponsors and Collaborators
Nantes University Hospital
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Principal Investigator: Charlotte AUTHIER, Doctor Health Care Centers of French Health Insurance in Saint-Nazaire
Principal Investigator: Didier GOXE Health Care Centers of French Health Insurance in La Roche sur Yon
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Responsible Party: Nantes University Hospital Identifier: NCT02354079    
Other Study ID Numbers: RC14_0400
First Posted: February 3, 2015    Key Record Dates
Last Update Posted: March 9, 2022
Last Verified: February 2022
Keywords provided by Nantes University Hospital:
Target Identification
Cardiovascular Disease
Additional relevant MeSH terms:
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Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism Disorders
Metabolic Diseases