In contrast, these experiments suggested that the rs45454293 polymorphism affects the binding of nuclear factors, protein complexes showing differential binding to the rs45454293T-allele. Taken together, the results of the haploChIP, transient transfections and EMSA studies suggest that rs45454293 is the functional polymorphism and that the lower transcriptional activity associated with the rs45454293T-allele is due to binding of one or more transcriptional repressor to the T-allele. Since the two TNFSF4 SNPs examined in the present study have not come up as genome-wide significant in the hitherto published genome-wide association studies for MI, it is likely that TNFSF4 does not belong to the group of major coronary artery disease susceptibility genes that survive the fairly conservative adjustments for multiple-testing applied on the hypothesisfree, high-density, high-coverage SNP genotyping in GWAS. However, the region containing the TNFSF4 gene has been found to be associated with celiac disease, a chronic inflammatory disease with a strong immune component and systemic lupus erythematosus, an autoimmune disease, which are likely to share common inflammatory pathways with atherosclerosis, the main underlying cause of MI. We have previously shown that Tnfsf4 Nutlin-3 Mdm2 inhibitor contributes to atheroma formation using both knockout and transgenic mice, and it is notable in this context that lesions in these strains are similar to early fatty streaks in humans, consisting primarily of foam cells without smooth muscle cells and fibrous cap formation. Furthermore, the mouse strains carried genetic variations in the Tnfsf4 promoter region that affected gene activity, as shown here for humans. However, unlike human plaques, the plaques found in the atherosclerosis-susceptible mice are not prone to rupture. Thus, it appears that harbouring this specific genetic variation in TNFSF4 promotes a pro-inflammatory state in humans that destabilizes the atherosclerotic plaque, making it particularly prone to rupture. For as yet unknown reasons, this effect seems to be gender-specific, being confined to women. The fact that TNFSF4 is expressed by several cell types suggests that TNFSF4 has more functions than the originally reported involvement in T-cell activation. Of cells present in the atherosclerotic lesion, both endothelial cells, macrophages, mast cells and SMCs express TNFSF4. Therefore, the observed genotype-phenotype associations could reflect the net effect of TNFSF4 actions in different cell types. Expression of TNFSF4 on different types of antigen-presenting cells might influence T-cell recognition of antigens, such as altered epitopes on MK-0683 oxidatively modified LDL particles. In addition, TNFSF4 expressed on mast cells may interact with TNFRSF4 on T-cells and stimulate their proliferation.