Association between genetic variants in the Coenzyme Q10 metabolism and Coenzyme Q10 status in humans

<p>Abstract</p> <p>Background</p> <p>Coenzyme Q₁₀(CoQ₁₀) is essential for mitochondrial energy production and serves as an antioxidants in extra mitochondrial membranes. The genetics of primary CoQ₁₀deficiency has been described in several studies, whereas the influence of common genetic variants on CoQ₁₀status is largely unknown. Here we tested for non-synonymous single-nucleotidepolymorphisms (SNP) in genes involved in the biosynthesis (CoQ3^G272S, CoQ6^M406V, CoQ7^M103T), reduction (NQO1^P187S, NQO2^L47F) and metabolism (apoE3/4) of CoQ₁₀and their association with CoQ₁₀status. For this purpose, CoQ₁₀serum levels of 54 healthy male volunteers were determined before (T₀) and after a 14 days supplementation (T₁₄) with 150 mg/d of the reduced form of CoQ₁₀.</p> <p>Findings</p> <p>At T₀, the CoQ₁₀level of heterozygous NQO1^P187Scarriers were significantly lower than homozygous S/S carriers (0.93 ± 0.25 μM versus 1.34 ± 0.42 μM, p = 0.044). For this polymorphism a structure homology-based method (PolyPhen) revealed a possibly damaging effect on NQO1 protein activity. Furthermore, CoQ₁₀plasma levels were significantly increased in apoE4/E4 genotype after supplementation in comparison to apoE2/E3 genotype (5.93 ± 0.151 μM versus 4.38 ± 0.792 μM, p = 0.034). Likewise heterozygous CoQ3^G272Scarriers had higher CoQ₁₀plasma levels at T₁₄compared to G/G carriers but this difference did not reach significance (5.30 ± 0.96 μM versus 4.42 ± 1.67 μM, p = 0.082).</p> <p>Conclusions</p> <p>In conclusion, our pilot study provides evidence that NQO1^P187Sand apoE polymorphisms influence CoQ₁₀status in humans.</p

The Cis-regulatory Logic of the Mammalian Photoreceptor Transcriptional Network

The photoreceptor cells of the retina are subject to a greater number of genetic diseases than any other cell type in the human body. The majority of more than 120 cloned human blindness genes are highly expressed in photoreceptors. In order to establish an integrative framework in which to understand these diseases, we have undertaken an experimental and computational analysis of the network controlled by the mammalian photoreceptor transcription factors, Crx, Nrl, and Nr2e3. Using microarray and in situ hybridization datasets we have produced a model of this network which contains over 600 genes, including numerous retinal disease loci as well as previously uncharacterized photoreceptor transcription factors. To elucidate the connectivity of this network, we devised a computational algorithm to identify the photoreceptor-specific cis-regulatory elements (CREs) mediating the interactions between these transcription factors and their target genes. In vivo validation of our computational predictions resulted in the discovery of 19 novel photoreceptor-specific CREs near retinal disease genes. Examination of these CREs permitted the definition of a simple cis-regulatory grammar rule associated with high-level expression. To test the generality of this rule, we used an expanded form of it as a selection filter to evolve photoreceptor CREs from random DNA sequences in silico. When fused to fluorescent reporters, these evolved CREs drove strong, photoreceptor-specific expression in vivo. This study represents the first systematic identification and in vivo validation of CREs in a mammalian neuronal cell type and lays the groundwork for a systems biology of photoreceptor transcriptional regulation

High-throughput elucidation of thrombus formation reveals sources of platelet function variability.

In combination with microspotting, whole-blood microfluidics can provide high-throughput information on multiple platelet functions in thrombus formation. Based on assessment of the inter- and intra-subject variability in parameters of microspot-based thrombus formation, we aimed to determine the platelet factors contributing to this variation. Blood samples from 94 genotyped healthy subjects were analyzed for conventional platelet phenotyping: i.e. hematologic parameters, platelet glycoprotein (GP) expression levels and activation markers (24 parameters). Furthermore, platelets were activated by ADP, CRP-XL or TRAP. Parallel samples were investigated for whole-blood thrombus formation (6 microspots, providing 48 parameters of adhesion, aggregation and activation). Microspots triggered platelet activation through GP Ib-V-IX, GPVI, CLEC-2 and integrins. For most thrombus parameters, inter-subject variation was 2-4 times higher than the intra-subject variation. Principal component analyses indicated coherence between the majority of parameters for the GPVI-dependent microspots, partly linked to hematologic parameters, and glycoprotein expression levels. Prediction models identified parameters per microspot that were linked to variation in agonist-induced αIIbβ3 activation and secretion. Common sequence variation of GP6 and FCER1G, associated with GPVI-induced αIIbβ3 activation and secretion, affected parameters of GPVI-and CLEC-2-dependent thrombus formation. Subsequent analysis of blood samples from patients with Glanzmann thrombasthenia or storage pool disease revealed thrombus signatures of aggregation-dependent parameters that were subject-dependent, but not linked to GPVI activity. Taken together, this high-throughput elucidation of thrombus formation revealed patterns of inter-subject differences in platelet function, which were partly related to GPVI-induced activation and common genetic variance linked to GPVI, but also included a distinct platelet aggregation component

Endocytosis of DNA-Hsp65 Alters the pH of the Late Endosome/Lysosome and Interferes with Antigen Presentation

BACKGROUND: Experimental models using DNA vaccine has shown that this vaccine is efficient in generating humoral and cellular immune responses to a wide variety of DNA-derived antigens. Despite the progress in DNA vaccine development, the intracellular transport and fate of naked plasmid DNA in eukaryotic cells is poorly understood, and need to be clarified in order to facilitate the development of novel vectors and vaccine strategies. METHODOLOGY AND PRINCIPAL FINDINGS: Using confocal microscopy, we have demonstrated for the first time that after plasmid DNA uptake an inhibition of the acidification of the lysosomal compartment occurs. This lack of acidification impaired antigen presentation to CD4 T cells, but did not alter the recruitment of MyD88. The recruitment of Rab 5 and Lamp I were also altered since we were not able to co-localize plasmid DNA with Rab 5 and Lamp I in early endosomes and late endosomes/lysosomes, respectively. Furthermore, we observed that the DNA capture process in macrophages was by clathrin-mediated endocytosis. In addition, we observed that plasmid DNA remains in vesicles until it is in a juxtanuclear location, suggesting that the plasmid does not escape into the cytoplasmic compartment. CONCLUSIONS AND SIGNIFICANCE: Taken together our data suggests a novel mechanism involved in the intracellular trafficking of plasmid DNA, and opens new possibilities for the use of lower doses of plasmid DNA to regulate the immune response

Cost-Effectiveness of New Cardiac and Vascular Rehabilitation Strategies for Patients with Coronary Artery Disease

Objective: Peripheral arterial disease (PAD) often hinders the cardiac rehabilitation program. The aim of this study was evaluating the relative cost-effectiveness of new rehabilitation strategies which include the diagnosis and treatment of PAD in patients with coronary artery disease (CAD) undergoing cardiac rehabilitation. Data Sources: Best-available evidence was retrieved from literature and combined with primary data from 231 patients. Methods: We developed a Markov decision model to compare the following treatment strategies: 1. cardiac rehabilitation only; 2. ankle-brachial index (ABI) if cardiac rehabilitation fails followed by diagnostic work-up and revascularization for PAD if needed; 3. ABI prior to cardiac rehabilitation followed by diagnostic work-up and revascularization for PAD if needed. Quality-adjusted-life years (QALYs), life-time costs (US $), incremental cost-effectiveness ratios (ICER), and gain in net health benefits (NHB) in QALY equivalents were calculated. A threshold willingness-to-pay of$75 000 was used. Results: ABI if cardiac rehabilitation fails was the most favorable strategy with an ICER of $44 251 per QALY gained and an incremental NHB compared to cardiac rehabilitation only of 0.03 QALYs (95$75 000/QALY. After sensitivity analysis, a combined cardiac and vascular rehabilitation program increased the success rate and would dominate the other two strategies with total lifetime costs of $30 246 a quality-adjusted life expectancy of 3.84 years, and an incremental NHB of 0.06 QALYs (95%CI:−0.24, 0.46) compared to current practice. The results were robust for other different input parameters. Conclusion: ABI measurement if cardiac rehabilitation fails followed by a diagnostic work-up and revascularization for PAD if needed are potentially cost-effective compared to cardiac rehabilitation only

A survey of tuberculosis infection control practices at the NIH/NIAID/DAIDS-supported clinical trial sites in low and middle income countries

BACKGROUND: Health care associated transmission of Mycobacterium tuberculosis (TB) is well described. A previous survey of infection control (IC) practices at clinical research sites in low and middle income countries (LMIC) funded by the National Institute of Allergy and Infectious Diseases (NIAID) conducting HIV research identified issues with respiratory IC practices. A guideline for TB IC based on international recommendations was developed and promulgated. This paper reports on adherence to the guideline at sites conducting or planning to conduct TB studies with the intention of supporting improvement. METHODS: A survey was developed that assessed IC activities in three domains: facility level measures, administrative control measures and environmental measures. An external site monitor visited each site in 2013–2014, to complete the audit. A central review committee evaluated the site-level survey and results were tabulated. Fisher’s exact test was performed to determine whether there were significant differences in practices at sites that had IC officers versus sites that did not have IC officers. Significance was assessed at p</=.05 RESULTS: Seven of thirty-three sites surveyed (22 %) had all the evaluated tuberculosis IC (TB IC) elements in place. Sixty-one percent of sites had an IC officer tasked with developing and maintaining TB IC standard operating procedures. Twenty-two (71 %) sites promptly identified and segregated individuals with TB symptoms. Thirty (93 %) sites had a separate waiting area for patients, and 26 (81 %) collected sputum within a specific well-ventilated area that was separate from the general waiting area. Sites with an IC officer were more likely to have standard operating procedures covering TB IC practices (p = 0.02) and monitor those policies (p = 0.02) and perform regular surveillance of healthcare workers (p = 0.02). The presence of an IC officer had a positive impact on performance in most of the TB IC domains surveyed including having adequate ventilation (p = 0.02) and a separate area for sputum collection (p = 0.02) CONCLUSIONS: Specific and targeted support of TB IC activities in the clinical research environment is needed and is likely to have a positive and sustained impact on preventing the transmission of TB to both health care workers and vulnerable HIV-infected research participants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-016-1579-y) contains supplementary material, which is available to authorized users

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Common germline polymorphisms associated with breast cancer-specific survival

Abstract Introduction Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. Methods A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. Results Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. Conclusions Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p