Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
Artikel i vetenskaplig tidskrift, 2008

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.

Alleles

CD44

Intracellular Signaling Peptides and Proteins

Insulin Receptor Substrate Proteins

genetics

Genetic

genetics

metabolism

Genotype

Endothelial Cells

genetics

metabolism

Antigens

Antigens

Foam Cells

Immunohistochemistry

cytology

Genetic

Reverse Transcriptase Polymerase Chain Reaction

Gene Expression Profiling

Cation Transport Proteins

genetics

genetics

genetics

metabolism

genetics

CD86

Phosphoproteins

metabolism

Genetic Predisposition to Disease

Atherosclerosis

Odds Ratio

metabolism

metabolism

metabolism

Risk Factors

Promoter Regions

Macrophages

genetics

pathology

cytology

cytology

Oligonucleotide Array Sequence Analysis

Humans

metabolism

metabolism

Polymorphism

Författare

Daniel Hägg

Göteborgs universitet

Margareta Jernås

Göteborgs universitet

Olov Wiklund

Göteborgs universitet

Dag Thelle

Björn Fagerberg

Göteborgs universitet

Per Eriksson

Anders Hamsten

Bob Olsson

Göteborgs universitet

Björn Carlsson

Göteborgs universitet

Lena M S Carlsson

Göteborgs universitet

Per-Arne Svensson

Göteborgs universitet

International Journal of Molecular Medicine

1107-3756 (ISSN)

Vol. 21 697-704

Ämneskategorier

MEDICIN OCH HÄLSOVETENSKAP

PubMed

18506362