Lack of association of two common polymorphisms on 9p21 with risk of coronary heart disease and myocardial infarction; results from a prospective cohort study

Background: Recent genome wide association (GWA) studies identified two Single Nucleotide Polymorphisms (SNP) (rs10757278 and rs10757274) in the region of the CDK2NA and CDK2NB genes to be consistently associated with the risks of coronary heart disease (CHD) and myocardial infarction (MI). We examined the SNPs in relation to the risk of CHD and MI in a large population based study of elderly population. Methods: The Rotterdam Study is a population-based, prospective cohort study among 7983 participants aged 55 years and older. Associations of the polymorphisms with CHD and MI were assessed by use of Cox proportional hazards analyses. Results: In an additive model, the age and sex adjusted hazard ratios (HRs) (95% confidence interval) for CHD and MI were 1.03 (0.90, 1.18) and 0.94 (0.82, 1.08) per copy of the G allele of rs10757274. The corresponding HRs were 1.03 (0.90, 1.18) and 0.93 (0.81, 1.06) for the G allele of rs10757278. The association of the SNPs with CHD and MI was not significant in any of the subgroups of CHD risk factors. Conclusion: We were not able to show an association of the studied SNPs with risks of CHD and MI. This may be due to differences in genes involved in the occurrence of CHD in young and older people

Sharing ICU Patient Data Responsibly Under the Society of Critical Care Medicine/European Society of Intensive Care Medicine Joint Data Science Collaboration: The Amsterdam University Medical Centers Database (AmsterdamUMCdb) Example.

OBJECTIVES: Critical care medicine is a natural environment for machine learning approaches to improve outcomes for critically ill patients as admissions to ICUs generate vast amounts of data. However, technical, legal, ethical, and privacy concerns have so far limited the critical care medicine community from making these data readily available. The Society of Critical Care Medicine and the European Society of Intensive Care Medicine have identified ICU patient data sharing as one of the priorities under their Joint Data Science Collaboration. To encourage ICUs worldwide to share their patient data responsibly, we now describe the development and release of Amsterdam University Medical Centers Database (AmsterdamUMCdb), the first freely available critical care database in full compliance with privacy laws from both the United States and Europe, as an example of the feasibility of sharing complex critical care data. SETTING: University hospital ICU. SUBJECTS: Data from ICU patients admitted between 2003 and 2016. INTERVENTIONS: We used a risk-based deidentification strategy to maintain data utility while preserving privacy. In addition, we implemented contractual and governance processes, and a communication strategy. Patient organizations, supporting hospitals, and experts on ethics and privacy audited these processes and the database. MEASUREMENTS AND MAIN RESULTS: AmsterdamUMCdb contains approximately 1 billion clinical data points from 23,106 admissions of 20,109 patients. The privacy audit concluded that reidentification is not reasonably likely, and AmsterdamUMCdb can therefore be considered as anonymous information, both in the context of the U.S. Health Insurance Portability and Accountability Act and the European General Data Protection Regulation. The ethics audit concluded that responsible data sharing imposes minimal burden, whereas the potential benefit is tremendous. CONCLUSIONS: Technical, legal, ethical, and privacy challenges related to responsible data sharing can be addressed using a multidisciplinary approach. A risk-based deidentification strategy, that complies with both U.S. and European privacy regulations, should be the preferred approach to releasing ICU patient data. This supports the shared Society of Critical Care Medicine and European Society of Intensive Care Medicine vision to improve critical care outcomes through scientific inquiry of vast and combined ICU datasets

Two years after molecular diagnosis of familial hypercholesterolemia: Majority on cholesterol-lowering treatment but a minority reaches treatment goal

Background: The risk of premature cardiovascular disease in patients with familial hypercholesterolemia (FH) can be profoundly reduced by cholesterol-lowering therapy, and current guidelines for FH advocate ambitious low-density lipoprotein cholesterol (LDL-C) goals. In the present study, we determined whether these goals are reflected in current clinical practice once FH has been diagnosed. Methodology/Principal Findings: In 2008, we sent questionnaires to all subjects (aged 18-65 years) who were molecularly diagnosed with FH in the year 2006 through the screening program in the Netherlands. Of these 1062 subjects, 781 completed the questionnaire (46% males; mean age: 42±12 years; mean LDL-C at molecular diagnosis (baseline): 4.1±1.3 mmol/L). The number of persons that used cholesterol-lowering therapy increased from 397 (51%) at baseline to 636 (81%) after diagnosis. Mean treated LDL-C levels decreased significantly to 3.2±1.1 mmol/L two years after diagnosis. Only 22% achieved the LDL-C target level of ≤2.5 mmol/L. Conclusions/Significance: The proportion of patients using cholesterol-lowering medication was significantly increased after FH diagnosis through

The Diabetes Pearl: Diabetes biobanking in The Netherlands

Contains fulltext : 109720.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Type 2 diabetes is associated with considerable comorbidity and severe complications, which reduce quality of life of the patients and require high levels of healthcare. The Diabetes Pearl is a large cohort of patients diagnosed with type 2 diabetes, covering different geographical areas in the Netherlands. The aim of the study is to create a research infrastructure that will allow the study of risk factors, including biomarkers and genetic determinants for severe diabetes complications. METHODS/DESIGN: Baseline examinations began November 2009 and will continue through 2012. By the end of 2012, it is expected that 7000 patients with type 2 diabetes will be included in the Diabetes Pearl cohort. To ensure quality of the data collected, standard operation procedures were developed and used in all 8 recruitment centers. From all patients who provide informed consent, the following information is collected: personal information, medication use, physical examination (antropometry, blood pressure, electrocardiography (ECG), retina photographs, ankle-brachial index, peripheral vibration perception), self-report questionnaire (socio-economic status, lifestyle, (family) history of disease, and psychosocial well-being), laboratory measurements (glucose, A1c, lipid profile, kidney function), biobank material (storage of urine and blood samples and isolated DNA). All gathered clinical data and biobank information is uploaded to a database for storage on a national level. Biobanks are maintained locally at all recruitment centers. DISCUSSION: The Diabetes Pearl is large-scale cohort of type 2 diabetes patients in the Netherlands aiming to study risk factors, including biomarkers and genetic markers, for disease deterioration and the development of severe diabetes complications. As a result of the well-designed research design and the national coverage, the Diabetes Pearl data can be of great value to national and international researchers with an interest in diabetes related research

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD

Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis.

OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants. RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes. RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant. CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Cardiac computed tomography imaging in familial hypercholesterolaemia: implications for therapy and clinical trials.

Purpose of reviewThe purpose of the present review is to summarize the potential clinical applications of computed tomographic angiography (CTA) in familial hypercholesterolemia so far and recent advances of CTA research in other high-risk patients.Recent findingsLong-term, aggressively statin-treated, asymptomatic familial hypercholesterolemia patients may still have dramatic coronary artery disease (CAD). A clear association between the presence and the extent of nonobstructive CAD and all-cause mortality was found in the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry. Notably, baseline statin therapy was associated with a significantly lower mortality for individuals with atherosclerotic plaque on CTA, but not for individuals with normal coronary arteries.SummaryCTA imaging has made clear that an increased plaque burden can be present even among asymptomatic, long-term aggressively statin-treated familial hypercholesterolemia patients. In the COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry, nonobstructive CAD predicted all-cause mortality and statin treatment improved the life span of persons with nonobstructive CAD. Clinical trials with CTA are required to develop and test identification of CAD and personalized treatment strategies for familial hypercholesterolemia

Outcome and complications after implantable cardioverter defibrillator therapy in hypertrophic cardiomyopathy: systematic review and meta-analysis

Background: Previous observational studies demonstrated that patients with hypertrophic cardiomyopathy at risk for sudden cardiac death (SCD) may benefit from implantable cardioverter defibrillator (ICD) therapy. A complete overview of outcome and complications after ICD therapy is currently not available. This study pools data from published studies on outcome and complications after ICD therapy in patients with hypertrophic cardiomyopathy. Methods and Results: A PubMed database search returned 27 studies on 16 cohorts reporting outcome and complications after ICD therapy in patients with hypertrophic cardiomyopathy. In case of >1 publications on a particular cohort, the publication with the largest number of patients was included in the meta-analysis. ICD interventions, complications, and mortality rates were extracted, pooled, and analyzed. There were 2190 patients (mean age, 42 years; 38% women), most of whom (83%) received an ICD for primary prevention of SCD. Risk factors for SCD were left ventricular wall thickness >= 30 mm (20%), family history of SCD (43%), nonsustained ventricular tachycardia (46%), syncope (41%), and abnormal blood pressure response (25%). During the 3.7-year follow-up, the annualized cardiac mortality rate was 0.6%, the noncardiac mortality rate was 0.4%, and the appropriate ICD intervention rate was 3.3%. The annualized inappropriate ICD intervention rate was 4.8% and the annualized ICD-related complication rate was 3.4%. Conclusions: This meta-analysis demonstrates a low cardiac and noncardiac mortality rate after ICD therapy in patients with hypertrophic cardiomyopathy. Appropriate ICD intervention occurred at a rate of 3.3%/year, thereby, most probably, preventing SCD. Inappropriate ICD intervention and complications are not uncommon