Factor VII Activating Protease Polymorphism (G534E) Is Associated with Increased Risk for Stroke and Mortality

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 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

Metabolic background determines the importance of NOS3 polymorphisms in restenosis after percutaneous coronary intervention:A study in patients with and without the metabolic syndrome

Variation in the NOS3 gene has been related to the development of restenosis. The Glu298Asp polymorphism has previously been investigated for its effect on NO levels and the development of restenosis. However, the variability of findings gave rise to the hypothesis that the functional significance of this polymorphism may only become manifest under conditions of endothelial dysfunction. Since patients with the metabolic syndrome are known to have endothelial dysfunction, we aimed to investigate if the significance of NOS3 polymorphisms may depend on the presence of the metabolic syndrome

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when = 50 years and symptomatic for <= 7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with <= 5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution

Platelet receptor P2RY12 haplotypes predict restenosis after percutaneous coronary interventions

The platelet receptor P2Y12 (gene symbol P2RY12) is involved in several processes that contribute to restenosis after percutaneous coronary interventions (PCI). Therefore, common variation in the P2Y12 gene may serve as a useful marker for risk stratification. We studied whether common variation in the platelet receptor P2Y12 gene affects the risk of restenosis after PCI. Comprehensive coverage of common variation in the P2Y12 gene was obtained by genotyping five haplotype-tagging SNPs (ht-SNPs) in 2,062 PCI-treated patients who received a stent and participated in the GENetic DEterminants of Restenosis (GENDER) Study. Haplotypes were inferred and their association with target vessel revascularization (TVR) was studied. Seven P2Y12 haplotypes were identified with an allelic frequency above 5% (designated here H1 to H7) of which two, (H5 and H7) were associated with a higher risk of TVR (hazard ratios [HR] = 1.4, 95% confidence interval [CI] = 1.0-2.0; and HR = 1.6, 95% CI = 1.2-2.0, respectively) than the reference P2Y12 haplotype (HI), which contains the common alleles of all five P2Y12 ht-SNPs. Our study shows that common variation in the P2Y12 gene predicts restenosis in PCI-treated patients

Toll-like receptor 4 gene polymorphisms show no association with the risk of clinical or angiographic restenosis after percutaneous coronary intervention

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 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

p27kip1-838C>A Single Nucleotide Polymorphism Is Associated With Restenosis Risk After Coronary Stenting and Modulates p27kip1 Promoter Activity

BACKGROUND: -The cyclin-dependent kinase inhibitor p27(kip1) is a key regulator of smooth muscle cell and leukocyte proliferation in vascular disease, including in-stent restenosis. We therefore hypothesized that common genetic variations or single nucleotide polymorphisms in p27(kip1) may serve as a useful tool in risk stratification for in-stent restenosis. Methods and Results-Three single nucleotide polymorphisms concerning the p27(kip1) gene (-838C>A, rs36228499; -79C>T, rs34330; +326G>T, rs2066827) were determined in a cohort of 715 patients undergoing coronary angioplasty and stent placement. We discovered that the p27(kip1)-838C>A single nucleotide polymorphism is associated with clinical in-stent restenosis; the -838AA genotype decreases the risk of target vessel revascularization (hazard ratio, 0.28; 95% confidence interval, 0.10 to 0.77). This finding was replicated in another cohort study of 2309 patients (hazard ratio, 0.61; 95% confidence interval, 0.40 to 0.93). No association was detected between this end point and the p27(kip1)-79C>T and +326G>T single nucleotide polymorphisms. We subsequently studied the functional importance of the -838C>A single nucleotide polymorphism and detected a 20-fold increased basal p27(kip1) transcriptional activity of the -838A allele containing promoter. Conclusions-Patients with the p27(kip1)-838AA genotype have a decreased risk of in-stent restenosis corresponding with enhanced promoter activity of the -838A allele of this cell-cycle inhibitor, which may explain decreased smooth muscle cell proliferatio

Vitamin D receptor: a new risk marker for clinical restenosis after percutaneous coronary intervention

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 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

The influence of established genetic variation in the haemostatic system on clinical restenosis after percutaneous coronary interventions

Since activation of the haemostatic system is an important feature of the wound healing response triggered by arterial injury, variations in genes involved in thrombus formation may play a role in restenosis after percutaneous coronary interventions (PCI). Therefore, our aim was to examine the relationship between polymorphisms that are known to play a role in the haemostatic system and the risk of clinical restenosis in the GENetic DEterminants of Restenosis (GENDER) study,a multicenter prospective study design that enrolled 3,104 consecutive patients after successful PCI.Target vessel revascularization (TVR) was the primary endpoint.All patients were genotyped for six polymorphisms in the Factor 11, Factor V, Factor VII and PAI- I genes. The PAI-I 4G variant was associated with an increased risk ofTVR.When compared to 5G/5G homozygotes, heterozygous patients were at higher risk for TVR (HR: 1.46, 95%Cl: 1.05-2.03), whereas patients with the 4G/4G genotype had an even further increased risk (HR: 1.69, 95%Cl: 1.19-2.41). In contrast, the factorV 506GIn (factor V Leiden) amino acid substitution was associated with a decreased risk ofTVR (HR: 0.41, 95%Cl: 0.19-0.86). Our findings indicate that polymorphisms in the factorV and PAI- I genes may play a role in the process of restenosis