Genome-wide Association Study of Susceptibility to Particulate Matter–Associated QT Prolongation

BACKGROUND: Ambient particulate matter (PM) air pollution exposure has been associated with increases in QT interval duration (QT). However, innate susceptibility to PM-associated QT prolongation has not been characterized. OBJECTIVE: To characterize genetic susceptibility to PM-associated QT prolongation in a multi-racial/ethnic, genome-wide association study (GWAS). METHODS: Using repeated electrocardiograms (1986–2004), longitudinal data on PM<10 μm in diameter (PM10), and generalized estimating equations methods adapted for low-prevalence exposure, we estimated approximately 2.5×106 SNP×PM10 interactions among nine Women’s Health Initiative clinical trials and Atherosclerosis Risk in Communities Study subpopulations (n=22,158), then combined subpopulation-specific results in a fixed-effects, inverse variance-weighted meta-analysis. RESULTS: A common variant (rs1619661; coded allele: T) significantly modified the QT-PM10 association (p=2.11×10−8). At PM10 concentrations >90th percentile, QT increased 7 ms across the CC and TT genotypes: 397 (95% confidence interval: 396, 399) to 404 (403, 404) ms. However, QT changed minimally across rs1619661 genotypes at lower PM10 concentrations. The rs1619661 variant is on chromosome 10, 132 kilobase (kb) downstream from CXCL12, which encodes a chemokine, stromal cell-derived factor 1, that is expressed in cardiomyocytes and decreases calcium influx across the L-type Ca2+ channel. CONCLUSIONS: The findings suggest that biologically plausible genetic factors may alter susceptibility to PM10-associated QT prolongation in populations protected by the U.S. Environmental Protection Agency’s National Ambient Air Quality Standards. Independent replication and functional characterization are necessary to validate our findings. https://doi.org/10.1289/EHP34

Patients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of Cardiology

Background: In order to influence every day clinical practice professional organisations issue management guidelines. Cross-sectional surveys are used to evaluate the implementation of such guidelines. The present survey investigated screening for glucose perturbations in people with coronary artery disease and compared patients with known and newly detected type 2 diabetes with those without diabetes in terms of their life-style and pharmacological risk factor management in relation to contemporary European guidelines. Methods: A total of 6187 patients (18–80 years) with coronary artery disease and known glycaemic status based on a self reported history of diabetes (previously known diabetes) or the results of an oral glucose tolerance test and HbA1c (no diabetes or newly diagnosed diabetes) were investigated in EUROASPIRE IV including patients in 24 European countries 2012–2013. The patients were interviewed and investigated in order to enable a comparison between their actual risk factor control with that recommended in current European management guidelines and the outcome in previously conducted surveys. Results: A total of 2846 (46%) patients had no diabetes, 1158 (19%) newly diagnosed diabetes and 2183 (35 %) previously known diabetes. The combined use of all four cardioprotective drugs in these groups was 53, 55 and 60%, respectively. A blood pressure target of 9.0% (>75 mmol/mol). Of the patients with diabetes 69% reported on low physical activity. The proportion of patients participating in cardiac rehabilitation programmes was low (≈40%) and only 27% of those with diabetes had attended diabetes schools. Compared with data from previous surveys the use of cardioprotective drugs had increased and more patients were achieving the risk factor treatment targets. Conclusions: Despite advances in patient management there is further potential to improve both the detection and management of patients with diabetes and coronary artery disease

Genes influencing coagulation and the risk of aneurysmal subarachnoid hemorrhage, and subsequent complications of secondary cerebral ischemia and rebleeding

We investigated whether genes influencing coagulation are associated with the occurrence of aneurysmal subarachnoid hemorrhage (SAH) and with secondary cerebral ischemia and rebleeding in patients with aneurysmal SAH. Genotyping for factor V Leiden (G1691A), prothrombin G20210A, methylenetetetrahydrofolate reductase (MTHFR) C677T, factor XIII subunit A Val34Leu, Tyr204Phe and Pro564Leu, and factor XIII subunit B His95Arg was performed in 208 patients with aneurysmal SAH and in 925 controls. Secondary cerebral ischemia occurred in 49 (24%) patients and rebleeding in 28 (14%) during their clinical course of 3 months after the aneurysmal SAH. The risk of aneurysmal SAH was assessed as odds ratio (OR) with 95% confidence interval (95% CI). The risk of secondary cerebral ischemia and rebleeding was assessed as hazard ratio (HR) with 95% CI using Cox regression. Carriers of the subunit B His95Arg factor XIII polymorphism had an increased risk of aneurysmal SAH with 23% of the patients homozygous or heterozygous for the variant allele compared to 17% of control subjects (OR 1.5, 95% CI 1.0-2.2). For the remaining genetic variants no effect on the risk of aneurysmal SAH could be demonstrated. A clear relation with the risk of secondary cerebral ischemia and of rebleeding could not be established for any of the genetic variants. We found that aneurysmal SAH patients are more often carriers of the subunit B His95Arg factor XIII polymorphism compared to controls. This suggests that carriers of the subunit B His95Arg factor XIII polymorphism have an increased risk of aneurysmal SAH. Larger studies should confirm our results. As aneurysmal SAH patients who died soon after admission could not be included in the present study, our results only apply to a population of patients who survived the initial hours after the hemorrhage. For the other studied genetic factors involved in coagulation, no association with the occurrence of aneurysmal SAH or with the occurrence of secondary cerebral ischemia or rebleeding after aneurysmal SAH could be demonstrated

Validating the German Version of the Quality of Relationship Inventory: Confirming the Three-Factor Structure and Report of Psychometric Properties

Research on psychosocial influences such as relationship characteristics has received increased attention in the clinical as well as social-psychological field. Several studies demonstrated that the quality of relationships, in particular with respect to the perceived support within intimate relationships, profoundly affects individuals' mental and physical health. There is, however, a limited choice of valid and internationally known assessments of relationship quality in Germany. We report the validation of the German version of the Quality of Relationships Inventory (QRI). First, we evaluated its factor structure in a representative German sample of 1.494 participants by means of confirmatory factor analysis. Our findings support the previously proposed three-factor structure. Second, importance and satisfaction with different relationship domains (family/children and relationship/sexuality) were linked with the QRI scales, demonstrating high construct validity. Finally, we report sex and age differences regarding the perceived relationship support, conflict and depth in our German sample. In conclusion, the QRI is a reliable and valid measurement to assess social support in romantic relationships in the German population

Global gene expression analysis of the mouse colonic mucosa treated with azoxymethane and dextran sodium sulfate

<p>Abstract</p> <p>Background</p> <p>Chronic inflammation is well known to be a risk factor for colon cancer. Previously we established a novel mouse model of inflammation-related colon carcinogenesis, which is useful to examine the involvement of inflammation in colon carcinogenesis. To shed light on the alterations in global gene expression in the background of inflammation-related colon cancer and gain further insights into the molecular mechanisms underlying inflammation-related colon carcinogenesis, we conducted a comprehensive DNA microarray analysis using our model.</p> <p>Methods</p> <p>Male ICR mice were given a single ip injection of azoxymethane (AOM, 10 mg/kg body weight), followed by the addition of 2% (w/v) dextran sodium sulfate (DSS) to their drinking water for 7 days, starting 1 week after the AOM injection. We performed DNA microarray analysis (Affymetrix GeneChip) on non-tumorous mucosa obtained from mice that received AOM/DSS, AOM alone, and DSS alone, and untreated mice at wks 5 and 10.</p> <p>Results</p> <p>Markedly up-regulated genes in the colonic mucosa given AOM/DSS at wk 5 or 10 included Wnt inhibitory factor 1 (<it>Wif1</it>, 48.5-fold increase at wk 5 and 5.7-fold increase at wk 10) and plasminogen activator, tissue (<it>Plat</it>, 48.5-fold increase at wk 5), myelocytomatosis oncogene (<it>Myc</it>, 3.0-fold increase at wk 5), and phospholipase A2, group IIA (platelets, synovial fluid) (<it>Plscr2</it>, 8.0-fold increase at wk 10). The notable down-regulated genes in the colonic mucosa of mice treated with AOM/DSS were the peroxisome proliferator activated receptor binding protein (<it>Pparbp</it>, 0.06-fold decrease at wk 10) and the transforming growth factor, beta 3 (<it>Tgfb3</it>, 0.14-fold decrease at wk 10). The inflammation-related gene, peroxisome proliferator activated receptor γ (<it>Pparγ </it>0.38-fold decrease at wk 5), was also down-regulated in the colonic mucosa of mice that received AOM/DSS.</p> <p>Conclusion</p> <p>This is the first report describing global gene expression analysis of an AOM/DSS-induced mouse colon carcinogenesis model, and our findings provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies against carcinogenesis.</p

Genome-wide association trans-ethnic meta-analyses identifies novel associations regulating coagulation Factor VIII and von Willebrand Factor plasma levels

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events

Workflow and Atlas System for Brain-Wide Mapping of Axonal Connectivity in Rat

Detailed knowledge about the anatomical organization of axonal connections is important for understanding normal functions of brain systems and disease-related dysfunctions. Such connectivity data are typically generated in neuroanatomical tract-tracing experiments in which specific axonal connections are visualized in histological sections. Since journal publications typically only accommodate restricted data descriptions and example images, literature search is a cumbersome way to retrieve overviews of brain connectivity. To explore more efficient ways of mapping, analyzing, and sharing detailed axonal connectivity data from the rodent brain, we have implemented a workflow for data production and developed an atlas system tailored for online presentation of axonal tracing data. The system is available online through the Rodent Brain WorkBench (www.rbwb.org; Whole Brain Connectivity Atlas) and holds experimental metadata and high-resolution images of histological sections from experiments in which axonal tracers were injected in the primary somatosensory cortex. We here present the workflow and the data system, and exemplify how the online image repository can be used to map different aspects of the brain-wide connectivity of the rat primary somatosensory cortex, including not only presence of connections but also morphology, densities, and spatial organization. The accuracy of the approach is validated by comparing results generated with our system with findings reported in previous publications. The present study is a contribution to a systematic mapping of rodent brain connections and represents a starting point for further large-scale mapping efforts

miR-143 Overexpression Impairs Growth of Human Colon Carcinoma Xenografts in Mice with Induction of Apoptosis and Inhibition of Proliferation

BACKGROUND: MicroRNAs (miRNAs) are aberrantly expressed in human cancer and involved in the (dys)regulation of cell survival, proliferation, differentiation and death. Specifically, miRNA-143 (miR-143) is down-regulated in human colon cancer. In the present study, we evaluated the role of miR-143 overexpression on the growth of human colon carcinoma cells xenografted in nude mice (immunodeficient mouse strain: N: NIH(s) II-nu/nu). METHODOLOGY/PRINCIPAL FINDINGS: HCT116 cells with stable miR-143 overexpression (Over-143) and control (Empty) cells were subcutaneously injected into the flanks of nude mice, and tumor growth was evaluated over time. Tumors arose ∼ 14 days after tumor cell implantation, and the experiment was ended at 40 days after implantation. miR-143 was confirmed to be significantly overexpressed in Over-143 versus Empty xenografts, by TaqMan® Real-time PCR (p<0.05). Importantly, Over-143 xenografts displayed slower tumor growth compared to Empty xenografts from 23 until 40 days in vivo (p<0.05), with final volumes of 928±338 and 2512±387 mm(3), respectively. Evaluation of apoptotic proteins showed that Over-143 versus Empty xenografts displayed reduced Bcl-2 levels, and increased caspase-3 activation and PARP cleavage (p<0.05). In addition, the incidence of apoptotic tumor cells, assessed by TUNEL, was increased in Over-143 versus Empty xenografts (p<0.01). Finally, Over-143 versus Empty xenografts displayed significantly reduced NF-κB activation and ERK5 levels and activation (p<0.05), as well as reduced proliferative index, evaluated by Ki-67 immunohistochemistry (p<0.01). CONCLUSIONS: Our results suggest that reduced tumor volume in Over-143 versus Empty xenografts may result from increased apoptosis and decreased proliferation induced by miR-143. This reinforces the relevance of miR-143 in colon cancer, indicating an important role in the control of in vivo tumor progression, and suggesting that miR-143 may constitute a putative novel therapeutic tool for colon cancer treatment that warrants further investigation

Quality of Life as an outcome in Alzheimer's disease and other dementias- obstacles and goals

<p>Abstract</p> <p>Background</p> <p>The number of individuals at risk for dementia will probably increase in ageing societies as will the array of preventive and therapeutic options, both however within limited economic resources. For economic and medical purposes valid instruments are required to assess disease processes and the efficacy of therapeutic interventions for different forms and stages of illness. In principal, the impact of illness and success of an intervention can be assessed with biomedical variables, e.g. severity of symptoms or frequency of complications of a disease. However, this does not allow clear judgement on clinical relevance or comparison across different diseases.</p> <p>Discussion</p> <p>Outcome model variables such as quality of life (QoL) or health care resource utilization require the patient to appraise their own well-being or third parties to set preferences. In Alzheimer's disease and other dementias the evaluation process performed by the patient is subject to the disease process itself because over progress of the disease neuroanatomical structures are affected that mediate evaluation processes.</p> <p>Summary</p> <p>Published research and methodological considerations thus lead to the conclusion that current QoL-instruments, which have been useful in other contexts, are ill-suited and insufficiently validated to play a major role in dementia research, decision making and resource allocation. New models integrating biomedical and outcome variables need to be developed in order to meet the upcoming medical and economic challenges.</p