DOCSLIB.ORG

A Gene Expression Study of the Glutamate-Nitric Oxide Pathway in Schizophrenia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Gene Expression Study of the Glutamate-Nitric Oxide Pathway in Schizophrenia P.320 A gene expression study of the glutamate-nitric oxide pathway in schizophrenia Kinoshita M1, Candemir E1, Kittel-Schneider S1, Reif, A1 and Freudenberg F1 1Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Laboratory for Translational Psychiatry, University Hospital Frankfurt BACKGROUND RESULTS Neuronal nitric oxide synthase (NOS-I) and its adaptor protein NOS1AP have Table 3. The results of linear regression analyses of NOS1AP expression previously been linked to schizophrenia. NOS1AP binding to NOS-I competes with NOS-I/PSD-95 interaction. Thus, increased NOS1AP expression, which has dPFC HPC Estimate (se) t value p value Estimate (se) t value p value been described in patients with schizophrenia [1] may reduce formation of the Diagnosis 0.0635 (0.043) 1.476 0.141 0.123 (0.089) 1.392 0.165 NOS-I/PSD-95/NMDA receptor complex, which may contribute to the Age of death 0.001 (0.001) 0.992 0.322 0.003 (0.003) 1.168 0.244 pathophysiology of schizophrenia [2]. Functionally, NOS1AP overexpression Gender 0.056(0.043) 1.292 0.197 - - - Brain pH -0.317 (0.079) -4.006 7.54E-05 -0.321 (0.148) -2.166 0.031 impacts on neuronal morphology and spine plasticity [3]. Importantly, NOS1AP Postmortem interval 0.004 (0.001) 3.712 2.40E-04 0.006 (0.002) 2.292 0.023 genetic variants have been associated with several schizophrenia-related endophenotypes [4]. Table 4. The results of χ2-tests AIMS Control Schizophrenia p value* NOS1AP expression higher lower higher lower We aimed to investigate the expression of NOS1, NOS1AP and associated dPFC 86(41.1%) 123(58.9%) 95(62.1%) 58(37.9%) 2.56E-0.4 genes in postmortem dorsolateral prefrontal cortex (dPFC) and hippocampus HPC 75(41.0%) 108(59.0%) 75(64.1%) 42(35.9%) 3.04E-04 (HPC) of schizophrenia patients. *Bonferroni corrected • There was a trend for higher expression of NOS1AP in schizophrenia samples. MATERIALS AND METHODS • In fact, higher frequencies of high NOS1AP levels were found in Data extraction: Access to whole-genome gene expression data of postmortem schizophrenia patients. brain tissues from patients with schizophrenia was obtained through dbGaP [5]. The used dataset contains Illumina® HumanHT-12 v4 mRNA expression data Figure 1. Box plots of glutamate-nitric oxide pathway related genes from HPC (134 schizophrenia and 281 controls) and dPFC (202 schizophrenia separated by NOS1AP expression levels and diagnosis and 347 controls). NOS1AP NOS1 CPE Background correction and normalization: Background correction was used dPFC HPC dPFC HPC dPFC HPC for adjusting the baseline probe signaling levels among probes. Quantile CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ * * * * * normalization followed by log2 transformation was performed after background correction. ”neqc” function of “limma” package in R was used. Sample selection: Control samples whose ages of death were under 17 and/or who had any positive history of antidepressant, mood stabilizer or benzodiazepine use were excluded. Samples with a positive history of cannabinoid or cocaine use were also excluded. Finally, samples with no information about cause of death, smoking, or alcohol, benzodiazepine, nicotine RASD1 DLG1 DLG4 or opiate use were excluded. The cause of death was classified as 1) natural, 2) dPFC HPC dPFC HPC dPFC HPC accidental, 3) suicide and 4) homicide. Table 1 shows the demographic details CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ * * * * * * * of samples after the exclusion. * * * * * Table 1. Demographic details of samples Ethnicity Number of Gender Mean age of Mean brain Mean postmortem (Caucasian/Asian/ samples (males/females) Death (SD) pH (SD) Interval (SD) African/Hispanic) 43.65 6.55 31.45 dPFC 209 147/62 90/111/5/3 (15.38) (0.26) (15.05) Control 42.62 6.54 30.85 HPC 183 129/54 71/106/3/3 (15.08) (0.28) (14.36) GRIN2A GRIA2 SYN1 50.33 6.40 38.53 dPFC 153 94/59 78/70/2/3 dPFC HPC dPFC HPC dPFC HPC (15.31) (0.25) (23.76) Schizophrenia CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ CON SCZ 51.04 6.36 36.69 HPC 117 76/41 48/65/2/2 * (15.91) (0.26) (19.57) * * * * * * * * * * Cause of death Smoking Alcohol use Benzodiazepine use Nicotine use Opiate use (natural/accidential/ (positive/negative) (positive/negative) (positive/negative) (positive/negative) (positive/negative) suicide/homicide) 52/157 12/197 168/13/0/28 0/209 50/159 7/202 47/136 11/172 144/9/0/ 0/183 45/138 6/177 110/43 15/138 103/17/31/2 12/141 72/81 16/137 84/33 12/105 81/10/24/2 7/110 64/53 11/106 Evaluation of potential confounding factors with NOS1AP expression and * p <0.05 after Bonferroni correction the linear regression analyses: Relations of potential confounding factors to NOS1AP expression were evaluated using single linear regression analyses. • NOS1AP, RASD1, DLG1, DLG4, GRIA1 and MAPK14 showed significant The evaluated factors were age of death, gender, ethnicity, brain pH, associations between lower and higher NOS1AP expression group in both postmortem interval, smoking history, alcohol use, cause of death, tissues. benzodiazepine use, nicotine use and opiate use. Age of death, brain pH and • GRIA2, GRIN2A and SYN1 showed the significant associations between the postmortem interval showed the significant relations with NOS1AP expression diagnosis in HPC. in HPC tissues and age of death, gender, brain pH and postmortem interval • GRIN2A in dPFC and GRIA2 and GRIN2B in HPC also showed the significant showed significant relations with NOS1AP expression in dPFC tissues. Linear associations between lower and higher NOS1AP expression group. regression analyses were used to assess the associations of diagnosis with NOS1AP expression. CONCLUSIONS Categorization of samples according to the NOS1AP expression levels: Median levels of NOS1AP expression in dPFC and HPC tissues were • Here we demonstrate that schizophrenia patients showed higher NOS1AP calculated. Samples with higher NOS1AP expression levels were included in expression levels than controls in dPFC and HPC. the higher group and samples with lower NOS1AP expression were categorized • We also demonstrate that genes in the glutamate-nitric oxide pathway may be in the lower group. 2 tests were conducted to compare the frequencies of χ modified by the NOS1AP expression levels. higher and lower samples of schizophrenia and control samples. Evaluation of NOS1AP expression levels: To assess the effect of NOS1AP • These results will be confirmed using postmortem brain tissues of expression level on the other genes which play roles in the glutamate-nitric schizophrenia from a separate cohort. NOS1AP oxide pathway, two-way ANOVAs were conducted with expression • Our results confirm and expand previous findings and may help to further group and diagnosis. Genes selected in this study were presented in table 2. All understand the molecular mechanisms contributing to schizophrenia and may statistical analyses were conducted by R ver. 3.2.3. eventually contribute to the development of targeted treatment strategies. Table 2. Glutamate-nitric oxide pathway related genes analysed in this study DISCLOSURE Genes Official full names Genes Official full names This study has been supported in part by the DFG (FR3420/2-2 to FF) and The Japanese Society of Clinical NOS1 Nitric oxide synthase 1 MAPK14 Mitogen-activated protein kinase 14 Neuropsychopharmacology (to MK). The funding agencies had no further role in study design or in the collection, analysis and NOS1AP Nitric oxide synthase 1 adaptor protein RASD1 Ras related dexamethasone induced 1 interpretation of data. CPE Carboxypeptidase E SYN1 Synapsin I REFERENCES DLG1 Discs large MAGUK scaffold protein 1 SCRIB Scribbled planar cell polarity protein 1. Freudenberg F et al., 2015. Neuronal nitric oxide synthase (NOS1) and its adaptor, NOS1AP, as a genetic risk factors for DLG3 MAP2K3 Discs large MAGUK scaffold protein 3 Mitogen-activated protein kinase kinase 3 psychiatric disorders. Genes Brain Behav. 14(1):46-63. DLG4 GUCY1B2 Discs large MAGUK scaffold protein 4 Guanylate cyclase 1 soluble subunit beta 2 2. Eastwood SL. 2005. Does the CAPON gene confer susceptibility to schizophrenia? PLoS Med. 2(10):e348. GRIA1 Glutamate ionotropic receptor AMPA type subunit 1 GUCY1A1 Guanylate cyclase 1 soluble subunit alpha 1 3. Candemir E et al., 2016. Interaction of NOS1AP with the NOS-I PDZ domain: Implications for schizophrenia-related GRIA2 Glutamate ionotropic receptor AMPA type subunit 2 GUCY1A2 Guanylate cyclase 1 soluble subunit alpha 2 alterations in dendritic morphology. Eur Neuropsychopharmacol. 26(4):741-55. GRIN2A Glutamate ionotropic receptor NMDA type subunit 2A GUCY1B1 Guanylate cyclase 1 soluble subunit beta 1 4. Greenwood TA et al., 2016. Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. Schizophr. Res. 170(1): 30-40. GRIN2B Glutamate ionotropic receptor NMDA type subunit 2B 5. https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000979.v1.p1 .
Load more

Recommended publications
  • 1 Evidence for Gliadin Antibodies As Causative Agents in Schizophrenia
    1 Evidence for gliadin antibodies as causative agents in schizophrenia. C.J.Carter PolygenicPathways, 20 Upper Maze Hill, Saint-Leonard’s on Sea, East Sussex, TN37 0LG [email protected] Tel: 0044 (0)1424 422201 I have no fax Abstract Antibodies to gliadin, a component of gluten, have frequently been reported in schizophrenia patients, and in some cases remission has been noted following the instigation of a gluten free diet. Gliadin is a highly immunogenic protein, and B cell epitopes along its entire immunogenic length are homologous to the products of numerous proteins relevant to schizophrenia (p = 0.012 to 3e-25). These include members of the DISC1 interactome, of glutamate, dopamine and neuregulin signalling networks, and of pathways involved in plasticity, dendritic growth or myelination. Antibodies to gliadin are likely to cross react with these key proteins, as has already been observed with synapsin 1 and calreticulin. Gliadin may thus be a causative agent in schizophrenia, under certain genetic and immunological conditions, producing its effects via antibody mediated knockdown of multiple proteins relevant to the disease process. Because of such homology, an autoimmune response may be sustained by the human antigens that resemble gliadin itself, a scenario supported by many reports of immune activation both in the brain and in lymphocytes in schizophrenia. Gluten free diets and removal of such antibodies may be of therapeutic benefit in certain cases of schizophrenia. 2 Introduction A number of studies from China, Norway, and the USA have reported the presence of gliadin antibodies in schizophrenia 1-5. Gliadin is a component of gluten, intolerance to which is implicated in coeliac disease 6.
    [Show full text]
  • Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients
    G C A T T A C G G C A T genes Article Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients Bénédicte Demeer 1,2,3,4 , Nicole Revencu 1,5, Raphael Helaers 1 , Cica Gbaguidi 6, Stéphanie Dakpe 3,4,6 , Geneviève François 7, Bernard Devauchelle 3,4,6,Bénédicte Bayet 8 and Miikka Vikkula 1,* 1 Human Molecular Genetics, de Duve Institute, University of Louvain, 1200 Brussels, Belgium; [email protected] (B.D.); [email protected] (N.R.); [email protected] (R.H.) 2 Center for Human Genetics, CLAD Nord de France, CHU Amiens-Picardie, 80054 Amiens, France 3 Université Picardie Jules Verne, EA CHIMERE, EA 7516, 80054 Amiens, France; [email protected] (S.D.); [email protected] (B.D.) 4 Facing Faces Institute, 80054 Amiens, France 5 Center for Human Genetics, Cliniques universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium 6 Department of Maxillofacial Surgery and Stomatology, Centre de Compétence Fentes et Malformations Faciales (MAFACE), CHU Amiens-Picardie, 80054 Amiens, France; [email protected] 7 Department of Pediatrics, Cliniques Universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium; [email protected] 8 Centre Labiopalatin, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, 1200 Brussels, Belgium; [email protected] * Correspondence: [email protected]; Tel.: +32-2-764-7490 Received: 6 September 2019; Accepted: 19 October 2019; Published: 22 October 2019 Abstract: Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity.
    [Show full text]
  • Chr21 Protein-Protein Interactions: Enrichment in Products Involved in Intellectual Disabilities, Autism and Late Onset Alzheimer Disease
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.11.872606; this version posted December 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease Julia Viard1,2*, Yann Loe-Mie1*, Rachel Daudin1, Malik Khelfaoui1, Christine Plancon2, Anne Boland2, Francisco Tejedor3, Richard L. Huganir4, Eunjoon Kim5, Makoto Kinoshita6, Guofa Liu7, Volker Haucke8, Thomas Moncion9, Eugene Yu10, Valérie Hindie9, Henri Bléhaut11, Clotilde Mircher12, Yann Herault13,14,15,16,17, Jean-François Deleuze2, Jean- Christophe Rain9, Michel Simonneau1, 18, 19, 20** and Aude-Marie Lepagnol- Bestel1** 1 Centre Psychiatrie & Neurosciences, INSERM U894, 75014 Paris, France 2 Laboratoire de génomique fonctionnelle, CNG, CEA, Evry 3 Instituto de Neurociencias CSIC-UMH, Universidad Miguel Hernandez-Campus de San Juan 03550 San Juan (Alicante), Spain 4 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA 5 Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Republic of Korea 6 Department of Molecular Biology, Division of Biological Science, Nagoya University Graduate School of Science, Furo, Chikusa, Nagoya, Japan 7 Department of Biological Sciences, University of Toledo, Toledo, OH, 43606, USA 8 Leibniz Forschungsinstitut für Molekulare Pharmakologie
    [Show full text]
  • Clinical Application of Chromosomal Microarray Analysis for Fetuses With
    Xu et al. Molecular Cytogenetics (2020) 13:38 https://doi.org/10.1186/s13039-020-00502-5 RESEARCH Open Access Clinical application of chromosomal microarray analysis for fetuses with craniofacial malformations Chenyang Xu1†, Yanbao Xiang1†, Xueqin Xu1, Lili Zhou1, Huanzheng Li1, Xueqin Dong1 and Shaohua Tang1,2* Abstract Background: The potential correlations between chromosomal abnormalities and craniofacial malformations (CFMs) remain a challenge in prenatal diagnosis. This study aimed to evaluate 118 fetuses with CFMs by applying chromosomal microarray analysis (CMA) and G-banded chromosome analysis. Results: Of the 118 cases in this study, 39.8% were isolated CFMs (47/118) whereas 60.2% were non-isolated CFMs (71/118). The detection rate of chromosomal abnormalities in non-isolated CFM fetuses was significantly higher than that in isolated CFM fetuses (26/71 vs. 7/47, p = 0.01). Compared to the 16 fetuses (16/104; 15.4%) with pathogenic chromosomal abnormalities detected by karyotype analysis, CMA identified a total of 33 fetuses (33/118; 28.0%) with clinically significant findings. These 33 fetuses included cases with aneuploidy abnormalities (14/118; 11.9%), microdeletion/microduplication syndromes (9/118; 7.6%), and other pathogenic copy number variations (CNVs) only (10/118; 8.5%).We further explored the CNV/phenotype correlation and found a series of clear or suspected dosage-sensitive CFM genes including TBX1, MAPK1, PCYT1A, DLG1, LHX1, SHH, SF3B4, FOXC1, ZIC2, CREBBP, SNRPB, and CSNK2A1. Conclusion: These findings enrich our understanding of the potential causative CNVs and genes in CFMs. Identification of the genetic basis of CFMs contributes to our understanding of their pathogenesis and allows detailed genetic counselling.
    [Show full text]
  • Downloads/ (Accessed on 17 January 2020)
    cells Review Novel Approaches for Identifying the Molecular Background of Schizophrenia Arkadiy K. Golov 1,2,*, Nikolay V. Kondratyev 1 , George P. Kostyuk 3 and Vera E. Golimbet 1 1 Mental Health Research Center, 34 Kashirskoye shosse, 115522 Moscow, Russian; [email protected] (N.V.K.); [email protected] (V.E.G.) 2 Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, 119334 Moscow, Russian 3 Alekseev Psychiatric Clinical Hospital No. 1, 2 Zagorodnoye shosse, 115191 Moscow, Russian; [email protected] * Correspondence: [email protected] Received: 5 November 2019; Accepted: 16 January 2020; Published: 18 January 2020 Abstract: Recent advances in psychiatric genetics have led to the discovery of dozens of genomic loci associated with schizophrenia. However, a gap exists between the detection of genetic associations and understanding the underlying molecular mechanisms. This review describes the basic approaches used in the so-called post-GWAS studies to generate biological interpretation of the existing population genetic data, including both molecular (creation and analysis of knockout animals, exploration of the transcriptional effects of common variants in human brain cells) and computational (fine-mapping of causal variability, gene set enrichment analysis, partitioned heritability analysis) methods. The results of the crucial studies, in which these approaches were used to uncover the molecular and neurobiological basis of the disease, are also reported. Keywords: schizophrenia; GWAS; causal genetic variants; enhancers; brain epigenomics; genome/epigenome editing 1. Introduction Schizophrenia is a severe mental illness that affects between 0.5% and 0.7% of the human population [1]. Both environmental and genetic factors are thought to be involved in its pathogenesis, with genetic factors playing a key role in disease risk, as the heritability of schizophrenia is estimated to be 70–85% [2,3].
    [Show full text]
  • T Cells + Cytokines in CD8 Activation and Induction of Proinflammatory
    Selective Phosphorylation of the Dlg1AB Variant Is Critical for TCR-Induced p38 Activation and Induction of Proinflammatory Cytokines in CD8 + T Cells This information is current as of September 29, 2021. Jillian Crocetti, Oscar Silva, Lisa A. Humphries, Michelle D. Tibbs and M. Carrie Miceli J Immunol 2014; 193:2651-2660; Prepublished online 6 August 2014; doi: 10.4049/jimmunol.1401196 Downloaded from http://www.jimmunol.org/content/193/6/2651 References This article cites 49 articles, 25 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/193/6/2651.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Selective Phosphorylation of the Dlg1AB Variant Is Critical for TCR-Induced p38 Activation and Induction of Proinflammatory Cytokines in CD8+ T Cells Jillian Crocetti,*,1 Oscar Silva,†,1 Lisa A.
    [Show full text]
  • Lipid Related Genes Altered in NASH Connect Inflammation in Liver Pathogenesis Progression to HCC: a Canonical Pathway
    Lipid related genes altered in NASH connect inflammation in liver pathogenesis progression to HCC: a canonical pathway Christophe Desterke1, Franck Chiappini2* 1 Inserm, U935, Villejuif, F-94800, France 2 Cell Growth and Tissue Repair (CRRET) Laboratory, Université Paris-Est Créteil (UPEC), EA 4397 / ERL CNRS 9215, F-94010, Créteil, France. Corresponding author: *Franck Chiappini. Laboratoire du CRRET (Croissance, Réparation et Régénération Tissulaires), Université Paris-Est Créteil, 61 avenue du Général de Gaulle F- 94010, Créteil Cedex, Val de Marne, France. Email address: [email protected]; Tel: +33(0)145177080; Fax: +33(0)145171816 Supplementary Information Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Supplementary Datasets Table S2: Expression fold change of lipid related genes found differentially expressed between NASH and healthy obese liver samples. Supplementary Datasets Table S3: Liver as principal filter for prioritization of lipid related genes found differentially expressed in NASH. Supplementary Datasets Table S4: Gene prioritization secondary filters (immunological, inflammation, liver pathogenesis progression) table found with lipid related genes differentially expressed in NASH. Supplementary Datasets Table S5: Identification of protein partners of YWHAZ gene using InnateDB database. Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Ranking of "lipidic" textmining Gene symbol
    [Show full text]
  • The Genetic Variation Rs12143842 in NOS1AP Increases Idiopathic
    www.nature.com/scientificreports OPEN The genetic variation rs12143842 in NOS1AP increases idiopathic ventricular tachycardia risk in Received: 21 December 2016 Accepted: 14 July 2017 Chinese Han populations Published: xx xx xxxx Ronfeng Zhang, Feifei Chen, Honjiu Yu, Lianjun Gao, Xiaomeng Yin, Yingxue Dong, Yanzong Yang & Yunlong Xia Genome-wide association studies identified that the common T of rs12143842 in NOS1AP is associated with a QT/QTc interval in European populations. In this study, we test the association between the variation rs12143842 in NOS1AP and idiopathic ventricular tachycardia (IVT). A case-control association study examining rs12143842 was performed in two independent cohorts. The Northern cohort enrolled 277 IVT patients and 728 controls from a Chinese Gene ID population. The Central cohort enrolled 301 IVT patients and 803 matched controls. Genotyping was performed using high-resolution melt analysis. The minor T allele of the rs12143842 SNP was significantly associated with decreased IVT risk in the Northern cohort (adjusted P = 0.024, OR 0.71(0.52~0.96)), and this association was replicated in an independent Central Gene ID cohort (adjusted P = 0.029, OR 0.78 (0.62~0.97)). The association was more significant in the combined population (adjustedP = 0.001, OR 0.76 (0.64~0.90)). The P values for the genotypic association were significant for the dominant (P < 0.001) and additive (P = 0.001) models. The minor T allele for the SNP rs12143842 in NOS1AP is significantly associated with IVT.NOS1AP might be a novel gene affecting IVT, and further functional studies should be performed.
    [Show full text]
  • Pathogenesis of Coronary Artery Disease: Focus on Genetic Risk Factors and Identification of Genetic Variants
    The Application of Clinical Genetics Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants Sergi Sayols-Baixeras Abstract: Coronary artery disease (CAD) is the leading cause of death and disability worldwide, Carla Lluís-Ganella and its prevalence is expected to increase in the coming years. CAD events are caused by the Gavin Lucas interplay of genetic and environmental factors, the effects of which are mainly mediated through Roberto Elosua cardiovascular risk factors. The techniques used to study the genetic basis of these diseases have evolved from linkage studies to candidate gene studies and genome-wide association studies. Cardiovascular Epidemiology and Genetics Research Group, Institut Linkage studies have been able to identify genetic variants associated with monogenic diseases, Hospital del Mar d’Investigacions whereas genome-wide association studies have been more successful in determining genetic Mèdiques, Barcelona, Spain variants associated with complex diseases. Currently, genome-wide association studies have identified approximately 40 loci that explain 6% of the heritability of CAD. The application of this knowledge to clinical practice is challenging, but can be achieved using various strategies, such as genetic variants to identify new therapeutic targets, personal genetic information to improve disease risk prediction, and pharmacogenomics. The main aim of this narrative review is to provide a general overview of our current understanding of the genetics of coronary artery disease and its potential clinical utility. Keywords: coronary artery disease, pathogenesis, genetic risk factors, genetic variants Introduction Coronary artery disease (CAD) is the principal individual cause of mortality and morbidity worldwide.
    [Show full text]
  • Effects of in Utero Exposure to Di-N-Butyl Phthalate on Testicular
    Article Effects of In Utero Exposure to Di‐n‐Butyl Phthalate on Testicular Development in Rat Tan Ma 1,2,†, Xiaoqin Yin 1,2,†, Ruitong Han 1,2, Jie Ding 1,2, Huan Zhang 3,*, Xiaodong Han 1,2,* and Dongmei Li 1,2,* 1 Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; [email protected] (T.M.); [email protected] (X.Y.); [email protected] (R.H.); [email protected] (J.D.) 2 Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China 3 Department of Clinical and Experimental Medicine, Linköping University, SE‐581 83 Linköping, Sweden * Correspondence: [email protected] (H.Z.); [email protected] (X.H.); [email protected] (D.L.) † These authors contributed equally to this work. Received: 17 October 2017; Accepted: 20 October 2017; Published: 24 October 2017 Abstract: Humans are inevitably exposed to ubiquitous phthalate esters (PAEs). In utero exposure to di‐n‐butyl phthalate (DBP) induces abnormal development of the testis and reproductive tract in male offspring, which correspond closely with the human condition of testicular dysgenesis syndrome (TDS)‐like syndrome. However, the underlying mechanisms have not been elucidated in detail. In this study, pregnant rats were orally exposed to either corn oil (controls) or DBP at three different doses by gavage during Gestational Days 12.5–21.5. Pathological examinations were performed for toxicity evaluation. Proliferation and apoptosis related proteins (ras related dexamethasone induced 1 (Rasd1), mitogen‐activated protein kinase kinases1/2 (MEK1/2), Bcl‐2, and Bax) were measured for mechanisms exploration.
    [Show full text]
  • Role of Estrogen and RAS Signaling in Repeated Implantation Failure
    BMB Rep. 2018; 51(5): 225-229 BMB www.bmbreports.org Reports Invited Mini Review Role of estrogen and RAS signaling in repeated implantation failure Kwonho Hong1 & Youngsok Choi2,* 1Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, 2Department of Biomedical Science, CHA University, Seongnam 13488, Korea In humans, hormonal regulation is crucial for the preparation RAS signal as well as the implications for patient with repeated of uterine environment leading to either successful implantation failure. implantation or menstrual cycle. Estrogen is a pivotal female steroid hormone that regulates the uterine dynamics along ESTROGEN SIGNALING with progesterone in the estrous and menstrual cycles in humans. Estrogen signals act via nuclear estrogen receptor or Estrogen production from the ovary during the estrous or membrane-bound receptor. The membrane-bound estrogen menstrual cycle receptor plays a crucial role in the rapid response of estrogen Estrogen exists in three forms such as estrone, estradiol, and in the uterine epithelium. Recently, RASD1 has received estriol (1, 2). Estrogen is produced in various tissues including attention as a novel signal transducer of estrogen in various the ovary, placenta, fat, and the liver in females (3, 4). It is the systems including female reproductive organs. In this review, primary source of estrogen production. Two different somatic we discuss the regulation of estrogen and RASD1 signaling in cells known as theca and granulosa cells surround the oocyte the uterus and also provide insights into RAS as a novel in the ovarian follicles (3-5). Estrogen biosynthesis depends on signaling molecule in repeated implantation failure. [BMB P450 aromatase enzyme activity, which catalyzes the Reports 2018; 51(5): 225-229] hydroxylation of estrogen precursors, adrostenedione or testosterone (Fig.
    [Show full text]
  • Single-Cell Transcriptome Profiling of the Kidney Glomerulus Identifies Key Cell Types and Reactions to Injury
    BASIC RESEARCH www.jasn.org Single-Cell Transcriptome Profiling of the Kidney Glomerulus Identifies Key Cell Types and Reactions to Injury Jun-Jae Chung ,1 Leonard Goldstein ,2 Ying-Jiun J. Chen,2 Jiyeon Lee ,1 Joshua D. Webster,3 Merone Roose-Girma,2 Sharad C. Paudyal,4 Zora Modrusan,2 Anwesha Dey,5 and Andrey S. Shaw1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background The glomerulus is a specialized capillary bed that is involved in urine production and BP control. Glomerular injury is a major cause of CKD, which is epidemic and without therapeutic options. Single-cell transcriptomics has radically improved our ability to characterize complex organs, such as the kidney. Cells of the glomerulus, however, have been largely underrepresented in previous single-cell kidney studies due to their paucity and intractability. Methods Single-cell RNA sequencing comprehensively characterized the types of cells in the glomerulus from healthy mice and from four different disease models (nephrotoxic serum nephritis, diabetes, doxo- rubicin toxicity, and CD2AP deficiency). Results Allcelltypesintheglomeruluswereidentified using unsupervised clustering analysis. Novel marker genes and gene signatures of mesangial cells, vascular smooth muscle cells of the afferent and efferent arteri- oles, parietal epithelial cells, and three types of endothelial cells were identified. Analysis of the disease models revealed cell type–specific and injury type–specific responses in the glomerulus, including acute activation of the Hippo pathway in podocytes after nephrotoxic immune injury. Conditional deletion of YAP or TAZ resulted in more severe and prolonged proteinuria in response to injury, as well as worse glomerulosclerosis.
    [Show full text]