Objective: Mixed results have been reported of matrix metalloproteinases (MMP) and their association with restenosis after percutaneous coronary intervention (PCI). The current study examines... Show moreObjective: Mixed results have been reported of matrix metalloproteinases (MMP) and their association with restenosis after percutaneous coronary intervention (PCI). The current study examines whether multiple single nucleotide polymorphisms (SNPs), covering the full genomic region of MMP2 and MMP3, were associated with restenosis in the GENDER study population. Methods and results: The GENetic DEterminants of Restenosis (GENDER) study enrolled 3104 consecutive patients after successful PCI. The primary endpoint was clinical restenosis, defined as target vessel revascularization (TVR), occurring in 9.8% of the patients. From the Hapmap database, 19 polymorphisms of MMP2 and 11 of MMP3 were selected. Furthermore, in a subpopulation, a genome-wide association analysis (GWA) was performed. No significant association was found with any of the investigated SNPs, including the previously reported 5A/6A polymorphism (rs3025058), with regard to TVR using single SNP analysis or haplotype analysis. Conclusion: We found no significant association of MMP2 or MMP3 with TVR with this SNP-broad gene approach. Although we did not test all the known polymorphisms of these genes, using tagging analyses we examined those SNPs covering all known haplotypes of MMP2 and MMP3 to conclude that these genes do not correlate with a genetic risk of coronary restenosis after successful PCI. Show less
Introduction. The FSAP-Marburg I polymorphism (1704G > A), which reduces FSAP activity, is associated with late complications of carotid stenosis in humans. Therefore, this study examines the... Show moreIntroduction. The FSAP-Marburg I polymorphism (1704G > A), which reduces FSAP activity, is associated with late complications of carotid stenosis in humans. Therefore, this study examines the influence of the Marburg I polymorphism and the closely linked Marburg II polymorphism (1280G > C) on various cardiovascular outcomes in two large independent study populations. Methods. The two Marburg polymorphisms in the HABP2 gene encoding FSAP were genotyped in a large population of elderly patients at risk for vascular disease (the PROSPER-study, n = 5804) and in a study population treated with a percutaneous coronary intervention (the GENDER-study, n = 3104). Results. In the PROSPER study, the Marburg I polymorphism was associated with an increased risk of clinical stroke (HR: 1.60, 95% CI: 1.13-2.28) and all-cause mortality (HR: 1.33, 95% CI: 1.04-1.71). In the GENDER study carriers of this variant seemed at lower risk of developing restenosis (HR: 0.59, 95% CI: 0.34-1.01). The Marburg II polymorphism showed similar but weaker results. Conclusion. The increase in stroke risk in Marburg I carriers could be due to differential effects on smooth muscle cells and on matrix metalloproteinases, thereby influencing plaque stability. The possible protective effect on restenosis could be the result of reduced activation of zymogens, which are involved in hemostasis and matrix remodeling. Show less
This thesis examines the impact of genetic and epigenetic factors on several aspects of vascular disease. Part 1 addresses the influence of genetic variation in genes involved in the different... Show moreThis thesis examines the impact of genetic and epigenetic factors on several aspects of vascular disease. Part 1 addresses the influence of genetic variation in genes involved in the different processes that lead to the occurrence of adverse events after percutaneous coronary intervention, mainly restenosis after bare metal stent placement, but also late acquired stent malapposition after implantation of a drug-eluting stent. Part 2 discusses the role of a relatively new area of research, which we refer to as 'epigenetic epidemiology', in restenosis and other aspects of coronary heart disease. In this part we show that polymorphisms in genes encoding lysine acetyltransferases, which are able to modify chromatin structure to allow gene transcription, can influence restenosis and mortality from coronary heart disease in several large prospective follow-up studies. Show less
Aims This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase ... Show moreAims This study was designed to investigate the counterbalancing influence of genetic variation in the promoter of the gene encoding P300/CBP associated factor (PCAF), a lysine acetyltransferase (KAT), on coronary heart disease (CHD) and mortality. Methods and results The association of genetic variation in the PCAF-gene with CHD, restenosis and mortality was investigated in three large cohorts. The results were combined to examine overall effects on CHD mortality and on restenosis risk. Compared with the homozygous -2481G allele in the PCAF promoter, a significant reduction in CHD mortality risk with the homozygous -2481C PCAF promoter allele was observed. A combined risk reduction for CHD death for the three studies was 21% (15-26%; p=8.13X10(-4)). In elderly patients (> 58 years) the effects were stronger. Furthermore, this PCAF allele was significantly associated with all-cause mortality (p=0.001). Functional analysis showed that nuclear factors interact in vitro with the oligonucleotides encompassing the -2481G/C polymorphism and that this interaction might be influenced by this polymorphism in the PCAF promoter. Moreover, modulation of PCAF gene expression was detectable upon cuff-placement in an animal model of reactive stenosis. Conclusion We showed in three large prospective studies that the -2481C allele in the PCAF promoter is associated with a significant survival advantage in elderly patients. Our observations promote the concept that epigenetic processes are under genetic control and that, other than environment, variation in genes encoding KATs may also determine susceptibility to CHD outcomes and mortality. Show less
Objective Restenosis after percutaneous coronary intervention (PCI) remains an issue even in the drug-eluting stent era. Genetic polymorphisms may provide insight in the pathogenesis of restenosis... Show moreObjective Restenosis after percutaneous coronary intervention (PCI) remains an issue even in the drug-eluting stent era. Genetic polymorphisms may provide insight in the pathogenesis of restenosis and may help in the stratification of patients at risk for restenosis. The aim of this study was to examine whether polymorphisms at the toll-like receptor 4 (TLR4) locus, that are associated with impaired innate immune system and with an increased risk of cardiovascular events, were associated with clinical and/or angiographic restenosis after PCI. Methods The GENetic Determinants of Restenosis (GENDER) project was a prospective, multicenter study that enrolled 3146 consecutive patients after successful PCI. Frequencies of the TLR4 896A/G (Asp299Gly; rs4986790) and 1196C/T (Thr399Ile; rs4986791) polymorphisms and haplotypes were assessed. Patients were followed up for 1 year and in a subgroup of 406 patients angiographic follow-up was obtained. Results We included a total of 2682 patients that underwent successful PCI. There was no association between genotypes and the risk of target vessel revascularization at 1-year or late luminal loss at 6-months angiographic follow-up (P = 0.53 and 0.44, respectively). Absence of association with target lesion revascularization and late luminal loss was replicated in the GEnetic risk factors for In-Stent Hyperplasia study Amsterdam (GEISHA) cohort study of 674 patients and in a subgroup of 550 patients with angiographic follow-up available (P = 0.26, and 0.86, respectively). Moreover, in both the studies, no significant differences between haplotypes A/C and G/T were observed for target vessel revascularization at late luminal loss. Conclusion Although inflammation has been implicated in the pathophysiology of restenosis, the 896A/G and 1196C/T polymorphisms or haplotypes based on these polymorphisms at the TLR4 locus are not associated with an increased risk of target vessel revascularization or angiographic restenosis after PCI. These polymorphisms are not useful for pre-PCI identification of patients at risk for restenosis. Pharmacogenetics and Genomics 20: 544-552 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Show less
Objective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been... Show moreObjective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been shown to be involved not only in bone metabolism but also in modulating immune responses and cell proliferation. Since the inflammatory response is implicated in restenosis, VDR-gene variants could therefore contribute to the risk of restenosis. Methods/results: Systematic genotyping for 15 haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene was performed with the high throughput TaqMan allelic discrimination assays in the Genetic Determinants of Restenosis (GENDER) population. A haplotype-based survival analysis revealed an association of haplotypes in blocks 2, 3 and 4 of the VDR-gene with the risk of clinical restenosis (p-values 0.01, 0.04 and 0.02 respectively). After adjustment for clinical risk factors for restenosis, the individual effect of the block 2 AA haplotype (p = 0.011) persisted. Conclusions: The present study indicates that VDR plays a role in restenosis after PCI. Therefore, VDR genotype may be used as risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Show less
Research into the pathologic mechanisms of neurodegenerative diseases has revealed that CREB binding protein (CBP) plays an important role in cognitive dysfunction. Loss of one copy of this gene... Show moreResearch into the pathologic mechanisms of neurodegenerative diseases has revealed that CREB binding protein (CBP) plays an important role in cognitive dysfunction. Loss of one copy of this gene leads to a syndrome with severe cognitive dysfunction. We investigated the association between four common variants in the CBP gene and cognitive function in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Baseline associations between genetic variation and cognitive function were assessed with linear regression. Longitudinal associations were assessed with linear mixed models. All analyses were adjusted for sex, age, education, country, version of test, and pravastatin use. The intron 4CT and intron 3AC polymorphisms in the CBP gene were associated with better cognitive performance at baseline and during follow-up. Furthermore, the haplotype with the variant alleles of these two polymorphisms also showed a protective effect on cognitive function in all cognitive domains (all p<0.03). Genetic variation in the CBP gene is associated with better cognitive performance in an elderly population. Future research is necessary to investigate the effect of these polymorphisms on the expression of CBP levels and how these polymorphisms affect the gene expression mediated by CBP. Show less
