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

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."

Details