Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
Journal article, 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
Author
Daniel Hägg
University of Gothenburg
Margareta Jernås
University of Gothenburg
Olov Wiklund
University of Gothenburg
Dag Thelle
Björn Fagerberg
University of Gothenburg
Per Eriksson
Anders Hamsten
Bob Olsson
University of Gothenburg
Björn Carlsson
University of Gothenburg
Lena M S Carlsson
University of Gothenburg
Per-Arne Svensson
University of Gothenburg
International Journal of Molecular Medicine
1107-3756 (ISSN) 1791244x (eISSN)
Vol. 21 6 697-704Subject Categories
MEDICAL AND HEALTH SCIENCES
PubMed
18506362