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.
Bibliographical noteFunding Information:
This work was supported by Israel Science Foundation Grant 1053/12 awarded to R.D. S.C. was supported by the Abisch-Frenkel Foundation for the Promotion of Life Sciences.
This work was supported by Israel Science Foundation Grant 1053/12 awarded to R.D. S.C. was supported by the Abisch-Frenkel Foundation for the Promotion of Life Sciences. Manuscript received 28 December 2018 and in revised form 21 June 2019. Published, JLR Papers in Press, August 6, 2019 DOI https://doi.org/10.1194/jlr.M092049
Copyright © 2019 Winther et al.