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

Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data

<p>Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.</p> <p>Methods: The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.</p> <p>Results: The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.</p> <p>Conclusion: This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.</p&gt

Candidate Gene Analysis of Arteriovenous Fistula Failure in Hemodialysis Patients

BACKGROUND AND OBJECTIVES: Arteriovenous fistula (AVF) failure remains an important cause of morbidity in hemodialysis patients. The exact underlying mechanisms responsible for AVF failure are unknown but processes like proliferation, inflammation, vascular remodeling, and thrombosis are thought to be involved. The current objective was to investigate the association between AVF failure and single nucleotide polymorphisms (SNPs) in genes related to these pathophysiologic processes in a large population of incident hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 479 incident hemodialysis patients were included between January 1997 and April 2004. Follow-up lasted 2 years or until AVF failure, defined as surgery, percutaneous endovascular intervention, or abandonment of the vascular access. Forty-three SNPs in 26 genes, related to proliferation, inflammation, endothelial function, vascular remodeling, coagulation, and calcium/phosphate metabolism, were genotyped. Relations were analyzed using Cox regression analysis. RESULTS: In total, 207 (43.2%) patients developed AVF failure. After adjustment, two SNPs were significantly associated with an increased risk of AVF failure. The hazard ratio (95% confidence interval) of LRP1 rs1466535 was 1.75 (1.15 to 2.66) and patients with factor V Leiden had a hazard ratio of 2.54 (1.41 to 4.56) to develop AVF failure. The other SNPs were not associated with AVF failure. CONCLUSIONS: In this large cohort of hemodialysis patients, only 2 of the 43 candidate SNPs were associated with an increased risk of AVF failure. Whether other factors, like local hemodynamic circumstances, are more important or other SNPs play a role in AVF failure remains to be elucidated

Candidate Gene Analysis of Mortality in Dialysis Patients

<div><p>Background</p><p>Dialysis patients have high cardiovascular mortality risk. This study aimed to investigate the association between SNPs of genes involved in vascular processes and mortality in dialysis patients.</p><p>Methods</p><p>Forty two SNPs in 25 genes involved in endothelial function, vascular remodeling, cell proliferation, inflammation, coagulation and calcium/phosphate metabolism were genotyped in 1330 incident dialysis patients. The effect of SNPs on 5-years cardiovascular and non-cardiovascular mortality was investigated.</p><p>Results</p><p>The mortality rate was 114/1000 person-years and 49.4% of total mortality was cardiovascular. After correction for multiple testing, <i>VEGF rs699947</i> was associated with all-cause mortality (HR1.48, 95% CI 1.14–1.92). The other SNPs were not associated with mortality.</p><p>Conclusions</p><p>This study provides further evidence that a SNP in the <i>VEGF</i> gene may contribute to the comorbid conditions of dialysis patients. Future studies should unravel the underlying mechanisms responsible for the increase in mortality in these patients.</p></div

Baseline characteristics.

<p>Baseline characteristics.</p

Cardiovascular and non-cardiovascular mortality.

<p>Cardiovascular and non-cardiovascular mortality.</p

Kaplan Meier survival curve for all-cause, cardiovascular and non-cardiovascular mortality for <i>VEGF rs699947</i>.

<p>Kaplan Meier survival curve for all-cause, cardiovascular and non-cardiovascular mortality for <i>VEGF rs699947</i>.</p

Significantly associated SNPs of the 6 top genes.

<p>SNP, single nucleotide polymorphism; Chr, chromosome; bp, base pair; MAF, minor allele frequency in control group; OR, odds ratio. The imputation quality indicates the average posterior probability for the most likely genotype generated by MACH, ranging from 0–1.</p

Q-Q plot for the GWAS after imputation on clinical restenosis in the GENDER study population. Lambda = 1.027.

<p>Q-Q plot for the GWAS after imputation on clinical restenosis in the GENDER study population. Lambda  = 1.027.</p