miRNA-dependent target regulation: functional characterization of single-nucleotide polymorphisms identified in genome-wide association studies of Alzheimer’s disease

Other miRNA targeting sites identified by less stringent analysis near rs7143400-C/G, rs2847655-T/C, rs610923-C/A and rs9909-G/C. A summary of the genes, PolymiRTSs, effects of minor alleles, targeting miRNAs and miRNA expression alterations observed in AD (when available; refer to the cited references). The grayed miRNAs were also found in the stringent screening described in Fig. 2a in the main text. (XLS 23 kb

Developmental expression of 4-repeat-Tau induces neuronal aneuploidy in Drosophila tauopathy models

Tau-mediated neurodegeneration in Alzheimer's disease and tauopathies is generally assumed to start in a normally developed brain. However, several lines of evidence suggest that impaired Tau isoform expression during development could affect mitosis and ploidy in post-mitotic differentiated tissue. Interestingly, the relative expression levels of Tau isoforms containing either 3 (3R-Tau) or 4 repeats (4R-Tau) play an important role both during brain development and neurodegeneration. Here, we used genetic and cellular tools to study the link between 3R and 4R-Tau isoform expression, mitotic progression in neuronal progenitors and post-mitotic neuronal survival. Our results illustrated that the severity of Tau-induced adult phenotypes depends on 4R-Tau isoform expression during development. As recently described, we observed a mitotic delay in 4R-Tau expressing cells of larval eye discs and brains. Live imaging revealed that the spindle undergoes a cycle of collapse and recovery before proceeding to anaphase. Furthermore, we found a high level of aneuploidy in post-mitotic differentiated tissue. Finally, we showed that overexpression of wild type and mutant 4R-Tau isoform in neuroblastoma SH-SY5Y cell lines is sufficient to induce monopolar spindles. Taken together, our results suggested that neurodegeneration could be in part linked to neuronal aneuploidy caused by 4R-Tau expression during brain development

BBADIS-16-507-R1 1 Integrative network analysis reveals time-dependent molecular events underlying left ventricular remodeling in post-myocardial infarction patients

International audienceTo elucidate the time-resolved molecular events underlying the LV remodeling (LVR) process, we developed a large-scale network model that integrates the 24 molecular variables (plasma proteins and non-coding RNAs) collected in the REVE-2 study at four time points (baseline, 1month, 3months and 1year) after MI. The REVE-2 network model was built by extending the set of REVE-2 variables with their mechanistic context based on known molecular interactions (1310 nodes and 8639 edges). Changes in the molecular variables between the group of patients with high LVR (>20%) and low LVR (<20%) were used to identify active network modules within the clusters associated with progression of LVR, enabling assessment of time-resolved molecular changes. Although the majority of molecular changes occur at the baseline, two network modules specifically show an increasing number of active molecules throughout the post-MI follow up: one involved in muscle filament sliding, containing the major troponin forms and tropomyosin proteins, and the other associated with extracellular matrix disassembly, including matrix metalloproteinases, tissue inhibitors of metalloproteinases and laminin proteins. For the first time, integrative network analysis of molecular variables collected in REVE-2 patients with known molecular interactions allows insight into time-dependent mechanisms associated with LVR following MI, linking specific processes with LV structure alteration. In addition, the REVE-2 network model provides a shortlist of prioritized putative novel biomarker candidates for detection of LVR after MI event associated with a high risk of heart failure and is a valuable resource for further hypothesis generation

Angiotensin Converting Enzyme and Angiotensin II Type 1 Receptor Polymorphisms in Patients with Coronary Aneurysms

BACKGROUND: Conflicting results have been reported regarding the association of gene polymorphisms in the renin-angiotensin system (RAS) with different aspects of coronary artery disease (CAD), such as myocardial infarction, neointimal hyperplasia or coronary artery vasomotion. Since previous studies have linked angiotensin II to aneurysmal disease, our study hypothesis was that RAS gene polymorphisms may be associated with aneurysm remodeling in response to CAD. METHODS: The study population was selected from a series of 3862 consecutive patients who underwent coronary angiography in our institution. One hundred and thirteen consecutive patients with at least one coronary aneurysm (CA) were compared to 226 randomized control patients without CA. DNA was extracted from white blood cells. The angiotensin-converting enzyme (ACE) I/D and angiotensin type 1 receptor (AT1-R) A/C polymorphisms were detected using previously published techniques. RESULTS: The distributions of the three ACE genotypes were similar in both groups: CA: 13%, 46%, and 41% for II, ID, and DD respectively; controls: 18%, 41%, and 41% for II, ID, and DD respectively, p = 0.45. The distributions of the three AT1-R genotypes were also similar in both groups: CA: 54%, 41%, and 5% for AA, AC, and CC respectively; controls: 55%, 33%, and 12%, for AA, AC, and CC respectively, p = 0.08. CONCLUSION: Our results provide further information on the role of RAS polymorphisms on specific mechanisms implicated in CAD. Although an activated RAS may theoretically promote aneurysm formation, the 2 RAS polymorphisms analyzed in this study are not associated with this process in coronary arteries

0098: Erythrocyte membrane phospholipid fatty acids, dairy intakes and cardiovascular risk

IntroductionThe impact of dairy fats on cardiovascular risk has been debated. Circulating Pentadecanoic (15:0) and heptadecanoic (17:0) saturated fatty acids are good biomarkers of dairy product consumption as they are mainly provided by dairy fats. We described the prevalence of cardiovascular risk factors according to erythrocyte membrane phospholipid content in 15:0 and 17:0 fatty acids.Methods402 women and men aged 45-64 were randomly selected in 2005-2007, from the general population of three French areas. Nutritional data were collected through a 3-day food record. Fatty acid content was measured in erythrocyte membrane phospholipids.ResultsErythrocyte membrane contents in 15:0 and 17:0 fatty acids significantly increased with the consumption of dairy products collected during the 3-day food record. Prevalence of hypertension significantly decreased from the lowest to the highest quartile of 15:0 erythrocyte content (48.1%; 33.3%; 29.9%; 25.5%; p=0.005). A similar trend was observed for metabolic syndrome prevalence (39.4%; 28.1%; 25.2%; 21.3%; p=0.029). Prevalence of hypertension, hypertriglyceridaemia, overweight and metabolic syndrome significantly decreased from the lowest to the highest quartile of 17:0 erythrocyte content (44.1%; 36.5%; 28.1%; 25.6%; p=0.020 for hypertension; 30.3%; 15.4%; 16.9%; 16.7%; p=0.017 for hypertriglyceridaemia; 68.1%; 58.7%; 46.6%; 44.4%; p=0.002 for overweight; and 43.2%; 26.9%; 22.5%; 17.8%; p<0.001 for metabolic syndrome). All these relationships remained significant after adjustment for age and gender. The link did not reach significance level for diabetes.ConclusionElevated erythrocyte membrane phospholipid contents in 15:0 and 17:0 saturated fatty acids are associated with a lower prevalence of the metabolic syndrome and several of its components. These results suggest that saturated fat intake should not be systematically associated with high cardiovascular risk and can be considered as part of a balanced diet

Frequency of fruit and vegetable consumption and coronary heart disease in France and Northern Ireland: the PRIME study

Fruit and vegetable consumption is associated with low CHD risk in the USA and Northern Europe. There is, in contrast, little information about these associations in other regions of Europe. The goal of the present study was to assess the relationship between frequency of fruit and vegetable intake and CHD risk in two European populations with contrasting cardiovascular incidence rates; France and Northern Ireland. The present prospective study was in men aged 50-59 years, free of CHD, who were recruited in France (n 5982) and Northern Ireland (n 2105). Fruit and vegetable intake was assessed by a food-frequency questionnaire. Incident cases of acute coronary events and angina were recorded over a 5-year follow-up. During follow-up there was a total of 249 ischaemic events. After adjustment on education level, smoking, physical activity, alcohol consumption, employment status, BMI, blood pressure, serum total and HDL-cholesterol, the relative risks (RR) of acute coronary events were 0·67 (95% CI 0·44, 1·03) and 0·64 (95% CI 0·41, 0·99) in the 2nd and 3rd tertiles of citrus fruit consumption, respectively (P for trend <0·03). Similar results were observed in France and Northern Ireland. In contrast, the RR of acute coronary events for ‘other fruit' consumption were 0·70 (95% CI 0·31, 1·56) and 0·52 (95% CI 0·24, 1·14) respectively in Northern Ireland (trend P<0·05) and 1·29 (95% CI 0·69, 2·4) and 1·15 (95% CI 0·68, 1·94) in France (trend P=0·5; interaction P<0·04). There was no evidence for any association between vegetable intake and total CHD events. In conclusion, frequency of citrus fruit, but not other fruits, intake is associated with lower rates of acute coronary events in both France and Northern Ireland, suggesting that geographical or related factors might affect the relationship between fruit consumption and CHD ris

The major element of 1-year prognosis in acute coronary syndromes is severity of initial clinical presentation: Results from the French MONICA registries

SummaryBackgroundWhile the death rate from acute coronary syndromes (ACS) has been in decline for more than 50years, out-of-hospital mortality remains high despite improvements in care.AimTo evaluate the importance of out-of-hospital mortality and identify the main predictors of in-hospital and 1-year mortality in France.MethodsAnalyses were based on data from the French MONICA population-based registry, which included all cases of ACS occurring in people aged 35–74years during 2006 in three geographic areas in France. We first evaluated out-of-hospital mortality; then, using data from patients with incident ACS who reached hospital alive, Cox models were performed to determine the main predictors of 1-year mortality. The number of attributable deaths was assessed for variables of interest.ResultsAfter 1-year follow-up, case-fatality was 29.3% for incident events (n=2547); the proportion of out-of-hospital deaths was 70.3%, and 91.5% of deaths occurred in the 28days following the ACS. On multivariable analysis, the number of attributable deaths associated with three scenarios (out-of-hospital life-and-death emergency, hospitalization before ACS occurrence, and lack of coronary angiography) was 130 (accounting for 59% of deaths occurring after reaching the hospital) during 1-year follow-up. These scenarios corresponded to patients with an initial severe clinical presentation in whom rates of use of specific treatments and invasive procedures were very low.ConclusionA large proportion of fatalities after an ACS occurs in the out-of-hospital phase. Moreover, the major component of 1-year mortality is associated with a poor prognosis at initial presentation. This finding highlights the importance of cardiovascular prevention, population education and better out-of-hospital emergency management in improving prognosis after an ACS