Abstract
BackgroundCoronary restenosis after percutaneous coronary intervention (PCI) still remains a significant limitation of the procedure. The causative mechanisms of restenosis have not yet been fully identified. The goal of the current study was to perform gene-set analysis of biological pathways related to inflammation, proliferation, vascular function and transcriptional regulation on coronary restenosis to identify novel genes and pathways related to this condition.MethodsThe GENetic DEterminants of Restenosis (GENDER) databank contains genotypic data of 556,099SNPs of 295 cases with restenosis and 571 matched controls. Fifty-four pathways, related to known restenosis-related processes, were selected. Gene-set analysis was performed using PLINK, GRASS and ALIGATOR software. Pathways with a p<0.01 were fine-mapped and significantly associated SNPs were analyzed in an independent replication cohort.ResultsSix pathways (cell-extracellular matrix (ECM) interactions pathway, IL2 signaling pathway, IL6 signaling pathway, platelet derived growth factor pathway, vitamin D receptor pathway and the mitochondria pathway) were significantly associated in one or two of the software packages. Two SNPs in the cell-ECM interactions pathway were replicated in an independent restenosis cohort. No replication was obtained for the other pathways.ConclusionWith these results we demonstrate a potential role of the cell-ECM interactions pathway in the development of coronary restenosis. These findings contribute to the increasing knowledge of the genetic etiology of restenosis formation and could serve as a hypothesis-generating effort for further functional studies.
Highlights
Interventional cardiology has advanced tremendously in recent years, restenosis after percutaneous coronary intervention (PCI) still remains a significant limitation of the procedure. [1] Restenosis is a complex disease for which the causative mechanisms have not yet been fully identified
Candidate gene approaches investigating restenosis have resulted in identification of genetic variation in genes involved in the inflammatory response [2,3] and genes related to vascular remodeling [4,5] and proliferation [6]
In 2012, our group analyzed the joint effect of the genetic variation of 36 previously described candidate genes of restenosis, demonstrating that the joint effect of all the single nucleotide polymorphisms (SNPs) in these genes together was significantly associated with restenosis development
Summary
Interventional cardiology has advanced tremendously in recent years, restenosis after percutaneous coronary intervention (PCI) still remains a significant limitation of the procedure. [1] Restenosis is a complex disease for which the causative mechanisms have not yet been fully identified. In 2012, our group analyzed the joint effect of the genetic variation of 36 previously described candidate genes of restenosis, demonstrating that the joint effect of all the single nucleotide polymorphisms (SNPs) in these genes together was significantly associated with restenosis development. The main explanation for this is likely the multifactorial nature of the disease and the small individual effect size of the SNPs. It has been described that instead of examining individual SNPs, analyzing the joint effect of multiple SNPs is a better method to find genetic variation in complex diseases.[9,10,11] Incorporating biological knowledge of the interplay of several genes within functional pathways may improve the power to detect associated genes not previously identified for their involvement. The goal of the current study was to perform gene-set analysis of biological pathways related to inflammation, proliferation, vascular function and transcriptional regulation on coronary restenosis to identify novel genes and pathways related to this condition
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