New Single Nucleotide Polymorphisms in the Shear Responsive MCP-1 Promoter Region in Atherosclerosis.
Background: Atherosclerosis represents a complex chronic inflammatory process influenced in part by genetic factors. Polymorphisms in the key regulators of inflammation are hypothesized to increase the susceptibility for the development of atheroma. Single nucleotide polymorphisms (SNPs) affect the secretion of inflammatory mediators such as monocyte chemoattractant protein one (MCP-1). MCP-1 has been shown to affect atherosclerosis development and SNPs affecting its secretion may affect the occurrence of atherosclerosis in humans. The aim of this study is to examine the frequency of SNPs in the promoter region of MCP-1 in patients with atherosclerosis versus controls. Methods:DNA was obtained from patients presenting for carotid endarterectomy and controls. A region of the MCP-1 promoter spanning -2746 to +440 bases relative to the transcriptional start site was sequenced. Results: The MCP-1 distal regulatory region was sequenced and two known SNPs were identified at base -2518 and base -2076 from the transcriptional start site. A “G” substitution at -2518 is associated with increased secretion of MCP-1. No association between atherosclerosis and these two SNP’s was observed. Two new SNPs consisting of a C/G substitution at bases -302 and -868 from the transcriptional start site were discovered. Allele frequency for the C -301 SNP represented 33%% of the control population and 61% of the atherosclerotic population. There was a trend toward higher C allele frequency in the atherosclerotic population (P=0.10). The power of this analysis (0.35) was limited by the relatively small control sample size (n=16). Conclusion: We report the discovery of two novel SNPs in the MCP-1 promoter region. The SNP at the -301 base site that is activated by shear forces such as elevated blood pressure. This region is a highly conserved region with a high prevalence of the -301 polymorphism suggesting some effect on gene function. Work is on going to characterize the frequency of the C allele in populations with atherosclerosis as well as its effect on MCP-1 secretion.