Proteomic study of macrophages exposed to oxLDL identifies a CAPG polymorphism associated with carotid atherosclerosis

Objective: Macrophages play a key role in the development of atherosclerosis. The objective of this observational study was to characterize the proteome of macrophages to identify proteins implicated in atherosclerosis. Methods: The proteome of macrophage exposed to oxidized low-density lipoprotein (LDL) was studied in a sample of 12 subjects with autosomal dominant hypercholesterolemia and analyzed according to carotid atherosclerosis. Carotid intima-media thickness (IMT), genotyping of the polymorphisms responsible for the amino acid change present in the identified proteins, and an association study was performed in a sample of 320 subjects with autosomal dominant hypercholesterolemia and 145 normolipemic controls. Results: Mass spectroscopy identified two proteins, gelsolin like capping protein (CapG) and glutathione-S-transferase omega 1 (GSTO1), with large variability among subjects which corresponded with two common genetic variants. The rs6886 polymorphism in CAPG was significantly associated with carotid IMT. Carriers of the minor allele in CAPG polymorphism presented less carotid IMT than noncarriers in the hypercholesterolemia group (mean and maximum internal carotid IMT p = 0.016 and p = 0.032, respectively). This effect was more important in subjects below 50 years old (mean and maximum internal carotid IMT p < 0.001). Conclusions: Association analysis revealed rs6886 polymorphism in CAPG to be associated with carotid IMT, suggesting that this polymorphism could modulate macrophages' response to oxidized LDL in subjects with hypercholesterolemia. (C) 2009 Elsevier Ireland Ltd. All rights reserved.