Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.

• Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.

Nyckelord

Alleles

Antigens

CD44

genetics

metabolism

Antigens

CD86

genetics

metabolism

Atherosclerosis

genetics

metabolism

pathology

Cation Transport Proteins

genetics

metabolism

Endothelial Cells

cytology

metabolism

Foam Cells

cytology

metabolism

Gene Expression Profiling

Genetic Predisposition to Disease

genetics

Genotype

Humans

Immunohistochemistry

Insulin Receptor Substrate Proteins

Intracellular Signaling Peptides and Proteins

genetics

metabolism

Macrophages

cytology

metabolism

Odds Ratio

Oligonucleotide Array Sequence Analysis

Phosphoproteins

genetics

metabolism

Polymorphism

Genetic

Promoter Regions

Genetic

genetics

Reverse Transcriptase Polymerase Chain Reaction

Risk Factors

Alleles

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)