TY - JOUR

T1 - Allele-specific regulation of MTTP expression influences the risk of ischemic heart disease

AU - Aminoff, Anna

AU - Ledmyr, Helena

AU - Thulin, Petra

AU - Lundell, Kerstin

AU - Nunez, Leyla

AU - Strandhagen, Elisabeth

AU - Murphy, Charlotte

AU - Lidberg, Ulf

AU - Westerbacka, Jukka

AU - Franco-Cereceda, Anders

AU - Liska, Jan

AU - Nielsen, Lars Bo

AU - Gåfvels, Mats

AU - Mannila, Maria Nastase

AU - Hamsten, Anders

AU - Yki-Järvinen, Hannele

AU - Thelle, Dag

AU - Eriksson, Per

AU - Borén, Jan

AU - Ehrenborg, Ewa

N1 - Keywords: Aged; Alleles; Base Sequence; CCAAT-Enhancer-Binding Proteins; Carrier Proteins; Case-Control Studies; Fatty Liver; Female; Gene Expression Regulation; Heart; Hela Cells; Humans; Liver; Macrophages; Male; Middle Aged; Monocytes; Myocardial Ischemia; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Response Elements

PY - 2010

Y1 - 2010

N2 - Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.

AB - Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.

U2 - 10.1194/jlr.M900195-JLR200

DO - 10.1194/jlr.M900195-JLR200

M3 - Journal article

C2 - 19546343

VL - 51

SP - 103

EP - 111

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 1

ER -