Study of cardiovAscular Contrasted Phenotypes in Patients With FamIliaI hypercholesteRolemia (SAFIR)

The main objective of SAFIR is to identify the atherosclerotic genetic factors in these patients, which will identify new therapeutic targets for the treatment of CV and Familial Hypercholesterolemia diseases. In addition, SAFIR will allow the identification of new CV protection biomarkers, which will be useful tools for the development of a personalized medicine for the management of dyslipidemias.

Study Overview

• Status: Completed
• Conditions: Homozygous Familial Hypercholesterolemia
• Intervention / Treatment: Genetic: Whole Genome Sequencing

Detailed Description

The objective of the SAFIR study is to perform non-invasive coronary vascular phenotyping of familial hypercholesterolemia (FH) families by performing a coronary calcium score and then to detect protective genetic factors in patients who do not have a significant atheroma despite a perturbed biological phenotype.

The investigators will also conduct biochemical, lipidemic and metabolomic analyzes to identify a signature of biomarkers protective of cardiovascular risk in FH patients.

The investigators will use the French FH register, which already includes 3889 patients, to identify these "protected" FH families within the main reference centers for the management of FH for inclusion and follow-up of patients.

• Study Type: Interventional
• Enrollment (Actual): 562
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Dijon, France, 29079
    • Le Bocage Hospital
  • Lille, France, 59037
    • CHRU de Lille
  • Lyon, France, 69677
    • Louis Pradel cardiovascular Hospital
  • Marseille, France, 13285
    • La Conception Hospital
  • Nantes, France, 44093
    • Nantes University Hospital
  • Paris, France, 75013
    • Pitie-Salpêtrière Hospital
  • Paris, France, 75012
    • Saint-Antoine Hospital
  • Rennes, France, 35033
    • Rennes University Hospital
  • Toulouse, France, 31059
    • Toulouse Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient agreeing to sign the consent of the study and the consent of biocollection
• Patient suffering from a familial hypercholesterolemia with a clinically-biologic score DLCN (Dutch Lipid Clinic Network, Annex 2)> 8 and / or a causative mutation identified in the LDL receptor genes, apolipoprotein B100 or Of PCSK9.
• Men ≥ 40 years of age; Female ≥ 50 years
• Patient affiliated to an existing social insurance

The inclusion criteria to be met in the population with known coronary atheroma:

• Subject in secondary prevention of an atheromatous disease: coronary event or ischemic heart disease, irrespective of the result of the coronary calcium score; Ischemic stroke with proven carotid atheromatosis; revascularization (angioplasty, bypass surgery) or amputation in PAD
• Primary prevention topic CV with calcium score ≥ 400 Agatston units

Inclusion criteria to be met in the population without cardiovascular risk:

- No cardiovascular event (including MI, coronary revascularization, angina, stroke &, Transiant ischemic attack of atheromatous origin, PAD) with: For women between 50 and 65 years, a nil calcium score * For women between 65 and 75 years of age, a calcium score** ≤ 10 Agatston units For women over 75 years of age, a calcium score** ≤ 20 Agatston units For men between 40 and 55 years of age, a nil calcium score* for men For men between 55 and 70 years of age, a calcium score** ≤ 10 Agatston units For men over 70 years of age, a calcium score** ≤ 20 Agatston units

• 40 year old men and 50 year old women: less than 6 months old
• 41 year old men and 51 year old women: under 1 year old
• 42 year old men and 52 year old women: under 2 years old
• 43 year old men and 53 year old women: under 3 years old

• 44 year old men and 54 year old women: under 4 years old

  • Less than 5 years

Inclusion criteria to be met in the related population with familial hypercholesterolemia :

• Patient agreeing to sign the consent of the study and the consent of biocollection
• Patient suffering from a familial hypercholesterolemia with a clinically-biologic score DLCN (Dutch Lipid Clinic Network, Annex 2)> 8 and / or a causative mutation identified in the LDL receptor genes, apolipoprotein B100 or Of PCSK9.
• Men or Female ≥ 30 years
• Patient affiliated to an existing social insurance

Inclusion criteria to be met in the related population without familial hypercholesterolemia :

• Patient agreeing to sign the consent of the study and the consent of biocollection
• Patient not suffering from a familial hypercholesterolemia related to one of the members of the population suffering from familial hypercholesterolemia without cardiovascular risk
• Men or Female ≥ 18 years
• Patient affiliated to an existing social insurance

Exclusion Criteria:

• Subject suffering from active cancer or progressive neoplasia
• Subject treated with recent corticosteroid therapy
• Subjects with unsubstituted or poorly controlled hypothyroidism (TSH> normal)
• Subject receiving immunosuppressive or anti-cancer treatment
• Subject refusing to participate
• Subjects under tutelage, curatorship or a safeguard of justice or without social insurance

The exclusion criterion for all populations except the related population without familial hypercholesterolemia:

- Subject with no "definite" familial hypercholesterolemia according to the DLCN score (≤8), after auction. The purpose of the auction will be to rule on the causal nature of an identified mutation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Atherosclerosis- resistance; FH Patient without atherosclerosis	Genetic: Whole Genome Sequencing; Whole Genome Sequencing Biomarkers analyses; Other Names: Biological analyzes
Other: Control; FH patient with atheroclerosis	Genetic: Whole Genome Sequencing; Whole Genome Sequencing Biomarkers analyses; Other Names: Biological analyzes
Other: the related population without familial hypercholesterolemia; No FH patient	Genetic: Whole Genome Sequencing; Whole Genome Sequencing Biomarkers analyses; Other Names: Biological analyzes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of genes associated with the resistance to development of coronary atherosclerosis in subjects with heterozygous familial hypercholesterolemia	Identification of functional genetic variants by a Whole Genome Sequencing (WGS) approach in case-control analysis (FH without and with advanced coronary atherosclerosis) and/or family analysis (protected and affected relatives)	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of new biochemical, lipidemic, metabolomic and metagenomic biomarkers associated with cardiovascular protection in FH patients.	Lipidic panel, phosphocalcic panel, Ceramides, Alipoproteins, Lp(a), lipidomic, LDL size, Phospholipids, TMAO, Carnitin, Cholin, microbiota, metabolomic, LDL Ox, Sterols, Isoprostan, oxidation, inflammation, cytokins, oxidative stress.	3 years
Association of arterial stiffness (reflected by the pulse wave velocity) with the development of coronary atherosclerosis in FH patients	Measurement of arterial stiffness measured by popmeter® (pulse wave velocity)	3 years
Association of atherosclerosis of supra-aortic trunks (AST) with the development of coronary atherosclerosis in FH patients	Measurement of ASD through arterial Doppler ultrasonography (Intra-media thickness (IMT), degree of stenosis (ESCT), plaque)	3 years
Association of atherosclerosis of the lower limbs with the development of coronary atherosclerosis (PAD) in FH patients	Measurement of lower extremity involvement by arterial doppler ultrasonography	3 years
Association between aortic valvular score and development of coronary atherosclerosis in FH patients	Measurement of coronary calcium score and aortic valvular score (optional) by a thoracic CT scan	3 years
Association between coronary calcium score and aortic valvular score in HF patients	Measurement of coronary calcium score and aortic valvular score (optional) by a thoracic CT scan	3 years

Collaborators and Investigators

• Sponsor: Nantes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2017
• Primary Completion (Actual): May 6, 2021
• Study Completion (Actual): May 6, 2021

Study Registration Dates

• First Submitted: July 26, 2017
• First Submitted That Met QC Criteria: July 26, 2017
• First Posted (Actual): July 31, 2017

Study Record Updates

• Last Update Posted (Actual): May 24, 2021
• Last Update Submitted That Met QC Criteria: May 21, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: RC17_0244

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No