Signature of Serum miR-199a/b in Coronary Artery Bypass Graft Surgery

Objective: microRNAs (miRNAs) have important potential as biomarkers in the diagnosis and prognosis of ischemia/reperfusion (I/R) injury in coronary artery bypass grafting surgery (CABG). This study investigated the relationship between preoperative (preop) and postoperative (post-op) cardiac parameters and miRNA expressions in CABG. Methods: We analyzed a total of 94 individuals (CABG, n= 46 and healthy control, n=48). Quantitative real-time polymerase chain reaction (qRT) was performed to determine plasma miRNA expressions (miR-21, miR-181a, miR-199a, miR-199b, and miR-320a-5p) in triplicates: before surgery, 1 hour after surgery, and 24 hours after surgery. The target genes and pathways of miRNA were determined using bioinformatic analysis. The biomarker potentials of miRNAs were evaluated with receiver operating characteristic (ROC) curve analysis. Results: All miRNAs were significantly downregulated (p \u3c 0.05). Troponin I, LVEF, CPK, and CK-MB were found to be statistically significant for operation groups (p \u3c 0.05). miRNA expressions and cardiac markers were associated with troponin I and/or CK-MB. In ROC analyses, miR-199a was a good diagnostic marker. CREBRF and ZNF704 genes may be a target for these miRNAs. Conclusions: Downregulation of miR-199a has a regulatory role in ischemia/reperfusion. They may contribute to CABG pathology through these two genes involved in signaling cascades to turn on protein response and ion binding

Screening for Copy Number Variations of the 15q13.3 Hotspot in CHRNA7 Gene and Expression in Patients with Migraines

Background: a migraine is a neurological disease. Copy number variation (CNV) is a phenomenon in which parts of the genome are repeated. We investigated the effects of the CNV and gene expression at the location 15q13.3 in the Cholinergic Receptor Nicotinic Alpha 7 Subunit (CHRNA7) gene, which we believe to be effective in the migraine clinic. Methods: we evaluated changes in CHRNA7 gene expression levels and CNV of 15q13.3 in patients with migraine (n = 102, with aura, n = 43; without aura, n = 59) according to healthy controls (n = 120) by q-PCR. The data obtained were analyzed against the reference telomerase reverse transcriptase (TERT) gene with the double copy number by standard curve analysis. Copy numbers were graded as a normal copy (2), gain (2>), and loss (<2). Results: we analyzed using the 2−ΔΔCT calculation method. The CHRNA7 gene was significantly downregulated in patients (p < 0.05). The analysis of CNV in the CHRNA7 gene was statistically significant in the patient group, according to healthy controls (p < 0.05). A decreased copy number indicates a dosage loss. However, no significant difference was observed among gain, normal, and loss copy numbers and expression values in patients (p > 0.05). The change in CNV was not associated with the downregulation of the CHRNA7 gene. Conclusion: Downregulation of the CHRNA7 gene may contribute to the formation of migraine by inactivation of the alpha-7 nicotinic receptor (α7nAChR). The association of CNV gains and losses with migraines will lead to better understanding of the molecular mechanisms and pathogenesis, to better define the disease, to be used as a treatment target

SNP Variation in MicroRNA Biogenesis Pathway Genes as a New Innovation Strategy for Alzheimer Disease Diagnostics: A Study of 10 Candidate Genes in an Understudied Population From the Eastern Mediterranean

Erdal, Mehmet Emin/0000-0002-6191-2930;WOS: 000383914600002PubMed: 26796812Alzheimer disease (AD) is a common complex neurodegenerative disorder accounting for nearly 50% to 70% of dementias worldwide. Yet the current diagnostic options for AD are limited. New diagnostic innovation strategies focusing on novel molecules and pathways are sorely needed. In this connection, microRNAs (miRNAs) are conserved small noncoding RNAs that regulate posttranscriptional gene expression and are vital for neuronal development and its functional sustainability. Conceivably, biological pathways responsible for the biogenesis of miRNAs represent a veritable set of upstream candidate genes that can be potentially associated with the AD pathophysiology. Notably, whereas functional single-nucleotide polymorphisms (SNPs) in miRNA biogenesis pathway genes have been studied in other complex diseases, surprisingly, virtually no such study has been conducted on their relevance in AD. Moreover, novel diagnostics identified in easily accessible peripheral tissues such as the whole blood samples represent the initial entry or gateway points on the biomarker discovery critical path for AD. To the best of our knowledge, we report here the first association study of functional SNPs, as measured by real-time PCR in 10 upstream candidate genes critically situated on the miRNA biogenesis pathway, in a large sample of AD patients (N=172) and healthy controls (N=109) in a hitherto understudied world population from the Mersin region of the Eastern Mediterranean. We observed a significant association between 2 candidate genes and AD, TARBP2 rs784567 genotype and AD ((2)=6.292, P=0.043), and a trend for RNASEN rs10719 genotype ((2)=4.528, P=0.104) and allele (P=0.035). Functional SNP variations in the other 8 candidate genes (DGCR8, XPO5, RAN, DICER1, AGO1, AGO2, GEMIN3, and GEMIN4) did not associate with AD in our sample. Given the putative biological importance of miRNA biogenesis pathways, these emerging data can provide a new foundation to stimulate future debate and genetic investigations of AD, focusing on new molecular mechanisms such as miRNA biogenesis, particularly in accessible peripheral tissues for novel molecular diagnostics for dementia.University of Mersin [BAP-SBE TB]Supported by an intramural research grant from the University of Mersin [BAP-SBE TB (S.G.Y.) 2010-4]

Can Peripheral MicroRNA Expression Data Serve as Epigenomic (Upstream) Biomarkers of Alzheimer's Disease?

Erdal, Mehmet Emin/0000-0002-6191-2930;WOS: 000381214300002PubMed: 27501295Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. However, biomarkers that require testing in the brain tissue pose a formidable practical barrier to AD diagnostic innovation. MicroRNAs (miRNAs) are responsible for control of gene expression at the posttranscriptional level and are essential for the function of neuronal networks and neuronal survival. miRNA expression can impact the regulation of APP (amyloid beta A4 precursor protein), PSEN1 (presenilin 1), PSEN2 (presenilin 2), and BACE1 (beta-secretase 1) genes in the brain that were previously implicated in AD pathophysiology. Little is known, however, on the extent to which peripheral tissue (e.g., whole blood) miRNA variation might offer clinical predictive value for AD. Moreover, few studies have examined multiple peripheral miRNA expression data at the same time. We report here, to the best of our knowledge, the first whole-blood-based and parallel study of seven miRNAs (hsa-miR-9-5p, hsa-miR-29a-3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-miR-107, hsa-miR-125a-3p, and hsa-miR-125b5p) in relation to AD susceptibility. Notably, these miRNAs are situated "upstream" to the genes implicated in AD. We measured the whole-blood miRNA expression by a real-time polymerase chain reaction in a large study sample (n = 281), comprising patients with AD (n = 172) and healthy controls (n = 109). A reduction in whole-blood expression of hsa-miR-9-5p, hsa-miR-106a-5p, hsa-miR-106b-5p, and hsa-miR-107 was significantly associated with an increased risk of AD (p 0.05). In conclusion, these observations warrant replication in larger samples while making a contribution to translational research, precision medicine, and biomarker literatures, by expanding the current efforts for AD diagnostic innovation to the realm of epigenomic pathways such as miRNA expression variation among patients.Mersin University (BAP-SBE TB) [2010-4]This study was supported by the intramural research fund of the Mersin University (BAP-SBE TB [S.G.Y.] 2010-4). This article is based on the work done in the first author's PhD thesis (S.G.Y.); it has never been published as a journal article, and it represents original data and research. The authors thank the research participants who volunteered their time for this study

Polymorphisms in the IL-6 and IL-6R receptor genes as new diagnostic biomarkers of acute appendicitis: a study on two candidate genes in pediatric patients with acute appendicitis

WOS: 000367511200002PubMed: 26714766Background: Acute appendicitis (AA) (OMIM: 107700) is an inflammatory disease which is characterized by appendiceal inflammation. Genetic and environmental factors contribute to the development of AA. Especially, multiple genetic factors appear to be promising in the explanation of etiopathogenesis of AA. IL-6 (Interleukin-6) is an inflammatory cytokine and IL-6 receptor (IL-6R) plays an important role in the immune response. IL-6 (-572G/C rs1800796) and IL-6R (1:G.154448302 T > C rs7529229) gene polymorphisms may have an impact on cytokine production, immune response and these gene polymorphisms may be used as inflammatory markers in the diagnosis of appendicitis. Method: A total of 75 children with appendicitis, and 75 healthy children were included in the study. DNA extracts were obtained from peripheral lymphocytes. Single-nucleotide polymorphisms (SNPs) were analysed using an automated SYBR (R) Green RT-PCR system in pediatric patients with appendicitis (n = 75) and healthy controls (n = 75). Results: The allele and genotype frequencies for IL-6 rs1800796 and IL-6R rs7529229 polymorphisms were not different between the study groups (p > 0.05). Any statistically significant differences as for age, sex and other laboratory factors were not detected between the patients with appendicitis for genotype-allele frequencies (p > 0.05). Still in analyses performed to determine correlations among age, and gender of the patients, routine laboratory parameters and allele-genotype frequencies, a statistically significant intergroup difference was not detected. Genotype and allele frequencies were consistent with Hardy-Weinberg equilibrium (HWE) in all groups. Discussion: This is the first study to investigate the effects of functional two polymorphisms on IL-6 and IL-6R genes in a pediatric patient group with AA risk. With this study we investigated the contribution of IL-6 (-572G/C rs1800796) and IL-6R (1:G.154448302 T > C rs7529229) polymorphisms on pathogenesis, and severity of AA in pediatric patients with AA: These results will guide further genetic researches to be performed on the role of IL-6 and IL-6R in AA. Conclusions: Given the putative biological importance of this SNPs, these emerging data can provide a new foundation to stimulate future debate and genetic investigations of AA, focusing on new molecular mechanisms such as other IL gene polymorphisms, particularly in accessible peripheral tissues for novel molecular diagnostics for appendicitis.Firat UniversityFirat University [FUBAP TF.14.73]This study was supported by the intramural research fund of the Firat University (FUBAP TF.14.73). The authors thank the research participants who volunteered their time for this study

Personalized medicine beyond genomics: alternative futures in big data-proteomics, environtome and the social proteome

No field in science and medicine today remains untouched by Big Data, and psychiatry is no exception. Proteomics is a Big Data technology and a next generation biomarker, supporting novel system diagnostics and therapeutics in psychiatry. Proteomics technology is, in fact, much older than genomics and dates to the 1970s, well before the launch of the international Human Genome Project. While the genome has long been framed as the master or elite executive molecule in cell biology, the proteome by contrast is humble. Yet the proteome is critical for life-it ensures the daily functioning of cells and whole organisms. In short, proteins are the blue-collar workers of biology, the down-to-earth molecules that we cannot live without. Since 2010, proteomics has found renewed meaning and international attention with the launch of the Human Proteome Project and the growing interest in Big Data technologies such as proteomics. This article presents an interdisciplinary technology foresight analysis and conceptualizes the terms environtome and social proteome. We define environtome as the entire complement of elements external to the human host, from microbiome, ambient temperature and weather conditions to government innovation policies, stock market dynamics, human values, political power and social norms that collectively shape the human host spatially and temporally. The social proteome is the subset of the environtome that influences the transition of proteomics technology to innovative applications in society. The social proteome encompasses, for example, new reimbursement schemes and business innovation models for proteomics diagnostics that depart from the once-a-life-time genotypic tests and the anticipated hype attendant to context and time sensitive proteomics tests. Building on the nesting principle for governance of complex systems as discussed by Elinor Ostrom, we propose here a 3-tiered organizational architecture for Big Data science such as proteomics. The proposed nested governance structure is comprised of (a) scientists, (b) ethicists, and (c) scholars in the nascent field of ethics-of-ethics, and aims to cultivate a robust social proteome for personalized medicine. Ostrom often noted that such nested governance designs offer assurance that political power embedded in innovation processes is distributed evenly and is not concentrated disproportionately in a single overbearing stakeholder or person. We agree with this assessment and conclude by underscoring the synergistic value of social and biological proteomes to realize the full potentials of proteomics science for personalized medicine in psychiatry in the present era of Big Data.Scientific and Technological Research Council of Turkey (TUBITAK Program)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [2232]; Wellcome TrustWellcome TrustEuropean Commission [WT103360MA]Supported by an interdisciplinary career investigator award from the Scientific and Technological Research Council of Turkey (TUBITAK 2232 Program) to Vural Ozdemir. The analysis is independent views of the authors and do not necessarily reflect the position of their affiliated institutions or the funders. The concepts of environtome and social proteome were conceptualized and coined by V.O. The authors thank the anonymous peer-reviewers for constructive critique. Edward S. Dove acknowledges the Wellcome Trust Senior Investigator Award entitled Confronting the Liminal Spaces of Health Research Regulation'', Award No: WT103360MA, PI: Graeme Laurie

Lack of association of DRD3 and CNR1 polymorphisms with premenstrual dysphoric disorders

Background: Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized with physical and affective symptoms during the luteal phase of susceptible women. Objective: The aim of this study was to investigate the association of Dopamine D3 receptor (DRD3) polymorphism, and Cannabinoid receptor Type 1 (CNR1) polymorphism with PMDD. Materials and Methods: Fifty one participants with documented PMDD according to the DSM IV criteria and 51 healthy controls were included in this cross sectional study. Symptom severity was measured with daily self-rating, monthly premenstrual assessment forms and psychiatric interviews. The genotyping of DRD3 receptor and Cannabinoid type 1 receptors were performed using Taqmanfluorogenic assay method. Results: Distribution of DRD3 and CNR1 polymorphism was not different between patients and controls. Conclusion: These findings do not support a major role of DRD3, and CNR1 polymorphisms in contributing to susceptibility to premenstrual dysphoric disorder