In search of a genetic explanation for LDLc variability in an FH family: Common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family

Michael Winther, Shoshi Shpitzen, Or Yaacov, Jakob Landau, Limor Oren, Linda Foroozan-Rosenberg, Naama Lev Cohain, Daniel Schurr, Vardiela Meiner, Auryan Szalat, Shai Carmi, Michael R. Hayden, Eran Leitersdorf, Ronen Durst*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1733-1740
Number of pages8
JournalJournal of Lipid Research
Volume60
Issue number10
DOIs
StatePublished - 2019

Bibliographical note

Publisher Copyright:
Copyright © 2019 Winther et al.

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