TY - JOUR
T1 - In search of a genetic explanation for LDLc variability in an FH family
T2 - Common SNPs and a rare mutation in MTTP explain only part of LDL variability in an FH family
AU - Winther, Michael
AU - Shpitzen, Shoshi
AU - Yaacov, Or
AU - Landau, Jakob
AU - Oren, Limor
AU - Foroozan-Rosenberg, Linda
AU - Cohain, Naama Lev
AU - Schurr, Daniel
AU - Meiner, Vardiela
AU - Szalat, Auryan
AU - Carmi, Shai
AU - Hayden, Michael R.
AU - Leitersdorf, Eran
AU - Durst, Ronen
N1 - Publisher Copyright:
Copyright © 2019 Winther et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072840541&partnerID=8YFLogxK
U2 - 10.1194/jlr.M092049
DO - 10.1194/jlr.M092049
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 31387896
AN - SCOPUS:85072840541
SN - 0022-2275
VL - 60
SP - 1733
EP - 1740
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 10
ER -