Journal
JOURNAL OF LIPID RESEARCH
Volume 60, Issue 10, Pages 1733-1740Publisher
ELSEVIER
DOI: 10.1194/jlr.M092049
Keywords
low density lipoprotein; genetics; cholesterol metabolism; diseases; dyslipidemia; gene expression; polymorphisms; genes in lipid dysfunction; low density lipoprotein; assembly; low density lipoprotein cholesterol; familial hypercholesterolemia; single nucleotide polymorphism; microsomal triglyceride transfer protein
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Funding
- Israel Science Foundation [1053/12]
- Abisch-Frenkel Foundation for the Promotion of Life Sciences
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We previously identified a highly consanguineous familial hypercholesterolemia (FH) family demonstrating segregation of the JD Bari mutation in the LDL receptor as well as a putative cholesterol-lowering trait. We aimed to identify genes related to the latter effect. LDL cholesterol (LDLc) values were normalized for FH affectation status, age, and gender. Using genome-wide SNP data, we examined whether known SNPs gleaned from a genome-wide association study could explain the variation observed in LDLc. Four individuals with markedly reduced LDL levels underwent whole exome sequencing. After prioritizing all potential mutations, we identified the most promising candidate genes and tested them for segregation with the lowering trait. We transfected a plasmid carrying the top candidate mutation, microsomal triglyceride transfer protein (MTTP) R634C, into COS-7 cells to test enzymatic activity. The SNP score explained 3% of the observed variability. MTTP R634C showed reduced activity (49.1 nmol/ml) compared with the WT allele (185.8 nmol/ml) (P = 0.0012) and was marginally associated with reduced LDLc in FH patients (P = 0.05). Phenotypic variability in a FH pedigree can only partially be explained by a combination of common SNPs and a rare mutation and a rare variant in the MTTP gene. LDLc variability in FH patients may have nongenetic causes.
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