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Morgan T.M.,Vanderbilt University | House J.A.,University of Missouri - Kansas City | Cresci S.,University of Washington | Jones P.,University of Missouri - Kansas City | And 17 more authors.
BMC Medical Genetics | Year: 2011

Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease. © 2011 Morgan et al; licensee BioMed Central Ltd. Source


Kleber M.E.,Medical Clinic V Nephrology | Koller L.,Medical University of Vienna | Goliasch G.,Medical University of Vienna | Sulzgruber P.,Medical University of Vienna | And 9 more authors.
Circulation: Heart Failure | Year: 2015

Background-Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. Methods and Results-Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.261.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal proB-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEFrelated comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.051.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWFNT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). Conclusions-vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients. © 2015 American Heart Association, Inc. Source


Marzi C.,Helmholtz Center for Environmental Research | Albrecht E.,Helmholtz Center for Environmental Research | Hysi P.G.,Kings College London | Lagou V.,University of Oxford | And 30 more authors.
PLoS Genetics | Year: 2010

Elevated levels of acute-phase serum amyloid A (A-SAA) cause amyloidosis and are a risk factor for atherosclerosis and its clinical complications, type 2 diabetes, as well as various malignancies. To investigate the genetic basis of A-SAA levels, we conducted the first genome-wide association study on baseline A-SAA concentrations in three population-based studies (KORA, TwinsUK, Sorbs) and one prospective case cohort study (LURIC), including a total of 4,212 participants of European descent, and identified two novel genetic susceptibility regions at 11p15.5-p13 and 1p31. The region at 11p15.5-p13 (rs4150642; p = 3.20 × 10-111) contains serum amyloid A1 (SAA1) and the adjacent general transcription factor 2 H1 (GTF2H1), Hermansky-Pudlak Syndrome 5 (HPS5), lactate dehydrogenase A (LDHA), and lactate dehydrogenase C (LDHC). This region explains 10.84% of the total variation of A-SAA levels in our data, which makes up 18.37% of the total estimated heritability. The second region encloses the leptin receptor (LEPR) gene at 1p31 (rs12753193; p = 1.22 × 10-11) and has been found to be associated with CRP and fibrinogen in previous studies. Our findings demonstrate a key role of the 11p15.5-p13 region in the regulation of baseline A-SAA levels and provide confirmative evidence of the importance of the 1p31 region for inflammatory processes and the close interplay between A-SAA, leptin, and other acute-phase proteins. © 2010 Marzi et al. Source


Baranyi A.,Medical University of Graz | Meinitzer A.,Clinical Institute of Medical and Chemical Laboratory Diagnostics | Stepan A.,Medical University of Graz | Putz-Bankuti C.,Medical University of Graz | And 4 more authors.
Psychotherapy and Psychosomatics | Year: 2013

Background: The aim of this prospective study was to gain a more comprehensive picture of the biopsychosocial effects of interferon (IFN) treatment of patients with chronic hepatitis C (HCV). The predictors of depressive development and changes in health-related quality of life, life satisfaction and cognitive ability were measured with the inclusion of the social context. Furthermore, the effects of IFN treatment on indoleamine 2,3-dioxygenase, the level of tryptophan supply in the brain, the development of neurotoxic kynurenine metabolites and the thyroid glands were investigated. Therefore, for the first time the conditions for the development of depressive episodes in HCV patients treated with IFN were examined over the entire period of treatment as well as 3 months later, applying a holistic biopsychosocial model. Method: Psychiatric and biological assessments were carried out at 6 different times: before, during (at 1, 3, 6 and 9 months) and after the end of IFN treatment. Results: During IFN treatment 22 (53.7%) of 41 patients fulfilled the criteria for a treatment-related depressive disorder at least once during treatment. Contributing factors are tryptophan depletion (tryptophan to competing amino acids quotient), increased neurotoxic challenge (kynurenine to kynurenic acid quotient), less social support, female gender, preexisting psychiatric vulnerability, means of transmission, low financial security, impaired sexual satisfaction, small circle of friends, impaired physical role, strong body pain, low general health and vitality, reduced social functioning, impaired mental health and impaired emotional role. Conclusions: The awareness of relevant risk factors of IFN treatment-induced depression is essential to develop preventative treatment strategies. © 2013 S. Karger AG, Basel. Source


Kniepeiss D.,Medical University of Graz | Wagner D.,Medical University of Graz | Wasler A.,Medical University of Graz | Tscheliessnigg K.-H.,Medical University of Graz | Renner W.,Clinical Institute of Medical and Chemical Laboratory Diagnostics
Wiener Klinische Wochenschrift | Year: 2013

Summary: Everolimus is an immunosuppressive drug metabolized by enzymes of the CYP family. A common variant of the CYP2C8 gene, CYP2C8*3, results in strongly decreased CYP2C8 activity, but its role for the pharmacogenetics of everolimus remains unclear. Aim of the present study was to examine the role of CYP2C8 variants in everolimus dose and drug levels after heart transplantation. The present study comprised 30 patients with everolimus based maintenance therapy after heart transplantation. CYP2C8 genotypes were determined and correlated with clinical data. In all, 21 subjects carried the CYP2C8*1/*1 genotype and 9 subjects carried the CYP2C8*1/ *3 genotype. Neither everolimus dose nor everolimus levels were associated with CYP2C8 genotype at any point of time (p < 0.05). During follow-up, graft rejection reactions were observed in two patients and infections were observed in seven patients. In one patient, type 2 diabetes was diagnosed during follow-up. None of these adverse events were significantly associated with CYP2C8 genotypes. We conclude that in adult patients after heart transplantation, CYP2C8 genotypes are not associated with dose requirements or levels of everolimus. © 2013 Springer-Verlag Wien. Source

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