Genetic inflammatory factors predict restenosis after percutaneous coronary interventions

Background - Restenosis is a negative effect of percutaneous coronary intervention (PCI). No clinical factors are available that allow good risk stratification. However, evidence exists that genetic factors are important in the restenotic process as well as in the process of inflammation, a pivotal factor in restenosis. Association studies have identified genes that may predispose to restenosis, but confirmation by large prospective studies is lacking. Our aim was to identify polymorphisms and haplotypes in genes involved in inflammatory pathways that predispose to restenosis. Methods and Results - The GENetic DEterminants of Restenosis ( GENDER) project is a multicenter prospective study, including 3104 consecutive patients after successful PCI. Forty-eight polymorphisms in 34 genes in pathways possibly involved in the inflammatory process were analyzed. The 16Gly variant of the beta(2)-adrenergic receptor gave an increased risk of target vessel revascularization (TVR). The rare alleles of the CD14 gene (- 260T/T), colony-stimulating factor 2 gene (117Thr/Thr), and eotaxin gene (- 1328A/A) were associated with decreased risk of TVR. However, through the use of multiple testing corrections with permutation analysis, the probability of finding 4 significant markers by chance was 12%. Conclusions - Polymorphisms in 4 genes considered involved in the inflammatory reaction showed an association with TVR after PCI. Our results may contribute to the unraveling of the restenotic process. Given the explorative nature of this analysis, our results need to be replicated in other studies

Tumor necrosis factor-alpha plays an important role in restenosis development

Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNF alpha, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER) project included 3104 patients who underwent a successful PCI. Systematic genotyping for six polymorphisms in the TNF alpha gene was performed. The role of TNF alpha in restenosis was also assessed in ApoE*3-Leiden mice, TNF alpha knockout mice, and by local delivery of a TNF alpha biosynthesis inhibitor, thalidomide. The -238G-1031T haplotype of the TNF alpha gene increased clinical and angiographic risk of restenosis (P = 0.02 and P = 0.002, respectively). In a mouse model of reactive stenosis, arterial TNF alpha mRNA was significantly time-dependently up-regulated. Mice lacking TNF alpha or treated locally with thalidomide showed a reduction in reactive stenosis (P = 0.01 and P = 0.005, respectively). Clinical and preclinical data indicate that TNF alpha plays an important role in restenosis. Therefore, TNF alpha genotype may be used as a risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Inhibition of TNF alpha may be an anti-restenotic target strategy