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

• 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Keyword

Aged

Alleles

Base Sequence

CCAAT-Enhancer-Binding Proteins

genetics

metabolism

Carrier Proteins

genetics

Case-Control Studies

Fatty Liver

genetics

metabolism

Female

Gene Expression Regulation

Heart

physiology

Hela Cells

Humans

Liver

metabolism

Macrophages

metabolism

Male

Middle Aged

Monocytes

metabolism

Myocardial Ischemia

genetics

Polymorphism

Single Nucleotide

Promoter Regions

Genetic

Response Elements

genetics

Publication and Content Type

ref (subject category)

art (subject category)