Objective: Susceptibility to atherosclerosis is affected by genetic factors, although the number of genes that are involved and to what extent remains unknown. It is plausible that many genes contribute in an intricate fashion, and that different mechanisms may result in atherosclerosis independently. The aim of this study was to search for potential susceptibility genes for the development of atherosclerosis.

Methods: Using DNA micorarray, we compared expression profiles from macrophages derived from 15 subjects with atherosclerosis (twelve men, three women) and 15 matched controls (twelve men, three women), both before and after treatment with mmLDL. Genes with an altered expression were genotyped in a population material consisting of 556 individuals with a history of coronary heart disease (CHD) and 553 matched controls.

Results: We found that the insulin receptor substrate 2 (IRS2) gene is expressed at higher levels in macrophages from individuals with atherosclerosis, both before (1.3-fold, P < 0.05) and after treatment with mmLDL (1.2-fold, P < 0.05). We analyzed an SNP located in the promoter region of IRS2, -759 from ATG, shifting from a C to a T, and found that individuals homozygous for C has an elevated risk of CHD, Odds ratio 1.312, 95% CI 1,027-1,677.

Conclusion: IRS2 gene expression is elevated in macrophages from subjects with atherosclerosis, and individuals homozygous for C has an increased the risk of CHD, indicating that IRS2 may play a role in the development of atherosclerosis.