Background:In the present study we investigated the effects of genetic variations in the C-C motif chemokine ligand 17 (CCL17) gene on serum CCL17 levels and risk of coronary artery disease (CAD).

Methods and Results:A case-control study was conducted to determine causal inferences amongCCL17single-nucleotide polymorphisms (SNPs), serum CCL17 levels, and risk of CAD. Luciferase assays, electrophoretic mobility shift assays (EMSA), and allele-specific quantitative chromatin immunoprecipitation (ChIP) assays were used to assess the function of the SNPs. In all, 947 participants (794 with CAD, 153 without CAD) were included in the study. The T allele in rs223828, located in intron of theCCL17gene, was associated with increased serum CCL17 levels as well as increased CAD risk. A causal inference test using mediation analysis suggested that rs223828 had a significant indirect casual effect on the increased risk of CAD mediated via serum CCL17 levels. Luciferase assays confirmed that the rs223828T allele enhancesCCL17promoter activity. Protein-DNA binding studies using EMSA and allele-specific quantitative ChIP assays indicated preferential activator protein-1 (AP-1) complex formation and recruitment with the rs223828 T allele compared with the C allele.

Conclusions:We propose that theCCL17SNP rs223828 is associated with increased risk of CAD, and that this site may be a potential AP-1 binding site.