The Rs599839 A>G Variant Disentangles Cardiovascular Risk
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Whole Exome Sequencing in ADHD Trios from Single and Multi-Incident Families Implicates New Candidate Genes and Highlights Polygenic Transmission
European Journal of Human Genetics (2020) 28:1098–1110 https://doi.org/10.1038/s41431-020-0619-7 ARTICLE Whole exome sequencing in ADHD trios from single and multi-incident families implicates new candidate genes and highlights polygenic transmission 1,2 1 1,2 1,3 1 Bashayer R. Al-Mubarak ● Aisha Omar ● Batoul Baz ● Basma Al-Abdulaziz ● Amna I. Magrashi ● 1,2 2 2,4 2,4,5 6 Eman Al-Yemni ● Amjad Jabaan ● Dorota Monies ● Mohamed Abouelhoda ● Dejene Abebe ● 7 1,2 Mohammad Ghaziuddin ● Nada A. Al-Tassan Received: 26 September 2019 / Revised: 26 February 2020 / Accepted: 10 March 2020 / Published online: 1 April 2020 © The Author(s) 2020. This article is published with open access Abstract Several types of genetic alterations occurring at numerous loci have been described in attention deficit hyperactivity disorder (ADHD). However, the role of rare single nucleotide variants (SNVs) remains under investigated. Here, we sought to identify rare SNVs with predicted deleterious effect that may contribute to ADHD risk. We chose to study ADHD families (including multi-incident) from a population with a high rate of consanguinity in which genetic risk factors tend to 1234567890();,: 1234567890();,: accumulate and therefore increasing the chance of detecting risk alleles. We employed whole exome sequencing (WES) to interrogate the entire coding region of 16 trios with ADHD. We also performed enrichment analysis on our final list of genes to identify the overrepresented biological processes. A total of 32 rare variants with predicted damaging effect were identified in 31 genes. At least two variants were detected per proband, most of which were not exclusive to the affected individuals. -
Sortilin Expression Is Essential for Pro-Nerve Growth Factor-Induced Apoptosis of Rat Vascular Smooth Muscle Cells
Sortilin expression is essential for pro-nerve growth factor-induced apoptosis of rat vascular smooth muscle cells. Campagnolo, Luisa; Costanza, Gaetana; Francesconi, Arianna; Arcuri, Gaetano; Moscatelli, Ilana; Orlandi, Augusto Published in: PLoS ONE DOI: 10.1371/journal.pone.0084969 2014 Link to publication Citation for published version (APA): Campagnolo, L., Costanza, G., Francesconi, A., Arcuri, G., Moscatelli, I., & Orlandi, A. (2014). Sortilin expression is essential for pro-nerve growth factor-induced apoptosis of rat vascular smooth muscle cells. PLoS ONE, 9(1), [e84969]. https://doi.org/10.1371/journal.pone.0084969 Total number of authors: 6 General rights Unless other specific re-use rights are stated the following general rights apply: Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Read more about Creative commons licenses: https://creativecommons.org/licenses/ Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove -
Prongf Induces Tnfα-Dependent Death of Retinal Ganglion Cells Through a P75ntr Non-Cell-Autonomous Signaling Pathway
ProNGF induces TNFα-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway Frédéric Lebrun-Juliena,1, Mathieu J. Bertrandb,1, Olivier De Backerc, David Stellwagend, Carlos R. Moralese, Adriana Di Polo a,2,3, and Philip A. Barker b,2 aDepartment of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; bCentre for Neuronal Survival, Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada; cFacultés Universitaires Notre-Dame de la Paix School of Medicine, University of Namur, Namur B-5000, Belgium; dCentre for Research in Neuroscience, Montreal, Quebec H3G 1A4; and eDepartment of Anatomy and Cell Biology McGill University, Montreal, Quebec H3A 2B2, Canada Edited by Moses V. Chao, Skirball Institute of Biomolecular Medicine, New York, New York, and accepted by the Editorial Board December 30, 2009 (received for review August 17, 2009) Neurotrophin binding to the p75 neurotrophin receptor (p75NTR) Müller glial cells. Therefore, proNGF-induced neuronal loss in the activates neuronal apoptosis following adult central nervous sys- adult retina occurs through a non-cell-autonomous mechanism. tem injury, but the underlying cellular mechanisms remain poorly defined. In this study, we show that the proform of nerve growth Results factor (proNGF) induces death of retinal ganglion cells in adult ProNGF Induces Death of Retinal Ganglion Cells in Adult Rodents. To rodents via a p75NTR-dependent signaling mechanism. Expression investigate whether proNGF promotes neuronal death in vivo, we of p75NTR in the adult retina is confined to Müller glial cells; there- first retrogradely labeled RGCs of adult rats by applying fluo- fore we tested the hypothesis that proNGF activates a non-cell- rogold to the surface of the superior colliculus and then provided autonomous signaling pathway to induce retinal ganglion cell a single intraocular injection of proNGF or vehicle. -
Association of the PSRC1 Rs599839 Variant with Coronary Artery Disease in a Mexican Population
medicina Communication Association of the PSRC1 rs599839 Variant with Coronary Artery Disease in a Mexican Population Martha Eunice Rodríguez-Arellano 1, Jacqueline Solares-Tlapechco 1, Paula Costa-Urrutia 1 , Helios Cárdenas-Hernández 1, Marajael Vallejo-Gómez 1, Julio Granados 2 and Sergio Salas-Padilla 3,* 1 Laboratorio de Medicina Genómica, Hospital Regional Lic. Adolfo López Mateos ISSSTE, Ciudad de Mexico 01030, Mexico; [email protected] (M.E.R.-A.); [email protected] (J.S.-T.); [email protected] (P.C.-U.); [email protected] (H.C.-H.); [email protected] (M.V.-G.) 2 División de Inmunogenética, Departamento de Trasplantes, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de Mexico 14080, Mexico; [email protected] 3 Servicio de Cardiología, Hospital Regional Lic. Adolfo López Mateos ISSSTE, Ciudad de Mexico 01030, Mexico * Correspondence: [email protected]; Tel.: +52-555-322-2200 Received: 3 July 2020; Accepted: 12 August 2020; Published: 26 August 2020 Abstract: Background and Objectives: Coronary artery disease (CAD) is a major health problem in México. The identification of modifiable risk factors and genetic biomarkers is crucial for an integrative and personalized CAD risk evaluation. In this work, we aimed to validate in a Mexican population a set of eight selected polymorphisms previously associated with CAD, myocardial infarction (MI), or dyslipidemia. Materials and Methods: A sample of 907 subjects (394 CAD cases and 513 controls) 40–80 years old was genotyped for eight loci: PSRC1 (rs599839), MRAS (rs9818870), BTN2A1 (rs6929846), MTHFD1L (rs6922269), CDKN2B (rs1333049), KIAA1462 (rs3739998), CXCL12 (rs501120), and HNF1A (rs2259816). The association between single nucleotide polymorphisms (SNPs) and CAD was evaluated by logistic regression models. -
NTR3/Sortilin [G11]: MC0188 Intended Use: for Research Use Only
Medaysis Enable Innovation DATA SHEET Mouse Anti-NTR3/Sortilin [G11]: MC0188 Intended Use: For Research Use Only Description: Neurotensin (NT) initiates an intracellular response by interacting with the G protein-coupled receptors NTR1 (NTS1 receptor, high affinity NTR) and NTR2 (NTS2 receptor, levocabastine-sensitive neurotensin receptor), and the type I receptor NTR3 (NTS3 receptor, sortilin-1, Gp95). NT has a wide distribution in regions of the brain and in peripheral tissues where NT receptors can contribute to hypotension, hyperglycemia, hypothermia, antinociception and regulation of intestinal motility and secretion. HL-60 cells express NTR1, which can couple to Gq, Gi/o, or Gs. Alternative splicing of rat NTR2 can generate a 5-transmembrane domain variant isoform that is co-expressed with the fulllength NTR2 throughout the brain and spinal cord. NTR3 activation in the murine microglial cell line N11 induces MIP-2, Specifications Clone: G11 Source: Mouse Isotype: IgG1k Reactivity: Human, mouse, rat Localization: Membrane, cytoplasm Formulation: Purified antibody in PBS pH7.4, containing BSA and ≤ 0.09% sodium azide (NaN3) Storage: Store at 2°- 8°C Applications: ELISA, IHC, IF, IP, WB Package: Description Catalog No. Size NTR3/Sortilin Concentrated MC0188 1 ml IHC Procedure* Positive Control Tissue: Brain Concentrated Dilution: 50-200 Pretreatment: Citrate pH6.0 or EDTA pH8.0, 15 minutes using Pressure Cooker, or 30-60 minutes using water bath at 95°-99°C Incubation Time and Temp: 30-60 minutes @ RT Detection: Refer to the detection system manual * Result should be confirmed by an established diagnostic procedure. FFPE human epididymis tissue stained with anti- NTR3/Sortilin using DAB References: 1. -
Independent and Epistatic Effects of Variants in VPS10-D Receptors on Alzheimer Disease Risk and Processing of the Amyloid Precursor Protein (APP)
Citation: Transl Psychiatry (2013) 3, e256; doi:10.1038/tp.2013.13 & 2013 Macmillan Publishers Limited All rights reserved 2158-3188/13 www.nature.com/tp Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP) C Reitz1,2,3, G Tosto2, B Vardarajan4, E Rogaeva5, M Ghani5, RS Rogers2, C Conrad2, JL Haines6, MA Pericak-Vance7, MD Fallin8, T Foroud9, LA Farrer4,10,11,12,13,14, GD Schellenberg15, PS George-Hyslop5,16,17, R Mayeux1,2,3,18,19,20 and the Alzheimer’s Disease Genetics Consortium (ADGC) Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain- containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer’s disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n ¼ 11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on c-secretase processing of APP. -
Apolipoprotein(A) Secretion Is Modulated by Sortilin, Proprotein Convertase Subtilisin/Kexin Type 9, and Microsomal Triglyceride Transfer Protein
Western University Scholarship@Western Electronic Thesis and Dissertation Repository 6-24-2019 10:30 AM Apolipoprotein(a) Secretion is Modulated by Sortilin, Proprotein Convertase Subtilisin/Kexin Type 9, and Microsomal Triglyceride Transfer Protein Justin Clark The University of Western Ontario Supervisor Koschinsky, Marlys L. Robarts Research Institute Graduate Program in Physiology and Pharmacology A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Justin Clark 2019 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Cardiovascular Diseases Commons Recommended Citation Clark, Justin, "Apolipoprotein(a) Secretion is Modulated by Sortilin, Proprotein Convertase Subtilisin/Kexin Type 9, and Microsomal Triglyceride Transfer Protein" (2019). Electronic Thesis and Dissertation Repository. 6310. https://ir.lib.uwo.ca/etd/6310 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Elevated plasma lipoprotein(a) (Lp(a)) levels are a causal risk factor for cardiovascular disease (CVD), but development of specific Lp(a) lowering therapeutics has been hindered by insufficient understanding of Lp(a) biology. For example, the location of the noncovalent interaction that precedes the extracellular disulfide linkage between apolipoprotein(a) (apo(a)) and apolipoprotein B-100 (apoB-100) in Lp(a) biosynthesis is unclear. In this study we modulated known intracellular regulators of apoB-100 production and then assessed apo(a) secretion from human HepG2 cells expressing 17-kringle (17K) apo(a) isoform variants using pulse-chase analysis. -
Autoantibodies As Potential Biomarkers in Breast Cancer
biosensors Review Autoantibodies as Potential Biomarkers in Breast Cancer Jingyi Qiu, Bailey Keyser, Zuan-Tao Lin and Tianfu Wu * ID Department of Biomedical Engineering, University of Houston, 3517 Cullen BLVD, SERC 2008, Houston, TX 77204, USA; [email protected] (J.Q.); [email protected] (B.K.); [email protected] (Z.-T.L.) * Correspondence: [email protected]; Tel.: +1-713-743-0142 Received: 14 June 2018; Accepted: 11 July 2018; Published: 13 July 2018 Abstract: Breast cancer is a major cause of mortality in women; however, technologies for early stage screening and diagnosis (e.g., mammography and other imaging technologies) are not optimal for the accurate detection of cancer. This creates demand for a more effective diagnostic means to replace or be complementary to existing technologies for early discovery of breast cancer. Cancer neoantigens could reflect tumorigenesis, but they are hardly detectable at the early stage. Autoantibodies, however, are biologically amplified and hence may be measurable early on, making them promising biomarkers to discriminate breast cancer from healthy tissue accurately. In this review, we summarized the recent findings of breast cancer specific antigens and autoantibodies, which may be useful in early detection, disease stratification, and monitoring of treatment responses of breast cancer. Keywords: autoantibody; breast cancer; early diagnosis; immunotherapy 1. Introduction Breast cancer is the prevailing cancer among women in developing and developed countries [1]. As such, screening and early diagnosis with respect to risk stratification are critical for prevention and early intervention of the disease, leading to better therapeutic outcomes [2,3]. Breast cancer itself is genetically heterogeneous and expresses a variety of aberrant proteins that, until recently, were un-utilizable. -
Identification of Subgroups Along the Glycolysis-Cholesterol Synthesis
Zhang et al. Human Genomics (2021) 15:53 https://doi.org/10.1186/s40246-021-00350-3 PRIMARY RESEARCH Open Access Identification of subgroups along the glycolysis-cholesterol synthesis axis and the development of an associated prognostic risk model Enchong Zhang1†, Yijing Chen2,3†, Shurui Bao4, Xueying Hou3, Jing Hu3, Oscar Yong Nan Mu5, Yongsheng Song1 and Liping Shan1* Abstract Background: Skin cutaneous melanoma (SKCM) is one of the most highly prevalent and complicated malignancies. Glycolysis and cholesterogenesis pathways both play important roles in cancer metabolic adaptations. The main aims of this study are to subtype SKCM based on glycolytic and cholesterogenic genes and to build a clinical outcome predictive algorithm based on the subtypes. Methods: A dataset with 471 SKCM specimens was downloaded from The Cancer Genome Atlas (TCGA) database. We extracted and clustered genes from the Molecular Signatures Database v7.2 and acquired co-expressed glycolytic and cholesterogenic genes. We then subtyped the SKCM samples and validated the efficacy of subtypes with respect to simple nucleotide variations (SNVs), copy number variation (CNV), patients’ survival statuses, tumor microenvironment, and proliferation scores. We also constructed a risk score model based on metabolic subclassification and verified the model using validating datasets. Finally, we explored potential drugs for high-risk SKCM patients. Results: SKCM patients were divided into four subtype groups: glycolytic, cholesterogenic, mixed, and quiescent subgroups. The glycolytic subtype had the worst prognosis and MGAM SNV extent. Compared with the cholesterogenic subgroup, the glycolytic subgroup had higher rates of DDR2 and TPR CNV and higher proliferation scores and MK167 expression levels, but a lower tumor purity proportion. -
Effect of Alzheimer's Disease Risk Variant Rs3824968 at SORL1 On
www.nature.com/scientificreports OPEN Effect of Alzheimer's Disease Risk Variant rs3824968 at SORL1 on Regional Gray Matter Volume and Received: 30 November 2015 Accepted: 01 March 2016 Age-Related Interaction in Adult Published: 21 March 2016 Lifespan Chu-Chung Huang1,6, Mu-En Liu2,3,4, Hung-Wen Kao5,8, Kun-Hsien Chou6, Albert C. Yang2,4,7, Ying-Hsiu Wang2, Tong-Ru Chen2, Shih-Jen Tsai2,4 & Ching-Po Lin1,6,8 Sortilin receptor 1 (SORL1) is involved in cellular trafficking of amyloid precursor protein and plays an essential role in amyloid-beta peptide generation in Alzheimer disease (AD). The major A allele in a SORL1 single nucleotide polymorphism (SNP), rs3824968, is associated with an increased AD risk. However, the role of SORL1 rs3824968 in the normal ageing process has rarely been examined in relation to brain structural morphology. This study investigated the association between SORL1 rs3824968 and grey matter (GM) volume in a nondemented Chinese population of 318 adults within a wide age range (21–92 years). Through voxel-based morphometry, we found that participants carrying SORL1 allele A exhibited significantly smaller GM volumes in the right posterior cingulate, left middle occipital, medial frontal, and superior temporal gyri. Considerable interaction between age and SORL1 suggested a detrimental and accelerated ageing effect of allele A on putamen. These findings provide evidence that SORL1 rs3824968 modulates regional GM volume and is associated with brain trajectory during the adult lifespan. The sortilin-related receptor gene (SORL1) encodes a mosaic protein belonging to at least two families: the vac- uolar protein sorting 10 domain-containing receptor family and the low density lipoprotein receptor family. -
The Rs599839 A>G Variant Disentangles
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 15 March 2021 doi:10.20944/preprints202103.0400.v1 Article The rs599839 A>G variant disentangles cardiovascular risk and hepatocellular carcinoma in NAFLD patients Meroni Marica PhD1,2, Longo Miriam MSc1,3, Paolini Erika MSc1,4, Alisi Anna PhD5, Miele Luca MD6, De Caro Emilia Rita MSc1, Pisano Giuseppina MD1, Maggioni Marco MD7, Soardo Giorgio MD8, Valenti Luca MD2,9, Fracanzani Anna Ludovica MD1,2, Dongiovanni Paola MSc1. 1 General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 2 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy; 3 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Italy; 4 Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy; 5 Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children Hospital, IRCCS, Rome, Italy; 6 Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; 7 Department of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 8 Clinic of Internal Medicine-Liver Unit Department of Medical Area (DAME) University School of Medicine, Udine, Italy and Italian Liver Foundation AREA Science Park - Basovizza Campus, Trieste, Italy. 9 Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano; * Correspondence: [email protected]. Phone: +39-02-5503-3467. Fax +39-02-5503-4229. Abstract: Background and Aims: Dyslipidemia and cardiovascular diseases (CAD) are comorbidi- Citation: PhD, M.M.; MSc, L.M.; ties of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular car- MSc, P.E.; PhD, A.A.; MD, M.L.; cinoma (HCC). -
Genome-Wide Enhancer Annotations Differ Significantly in Genomic Distribution, Evolution, and Function
Benton et al. BMC Genomics (2019) 20:511 https://doi.org/10.1186/s12864-019-5779-x RESEARCH ARTICLE Open Access Genome-wide enhancer annotations differ significantly in genomic distribution, evolution, and function Mary Lauren Benton1, Sai Charan Talipineni2, Dennis Kostka2,3* and John A. Capra1,4* Abstract Background: Non-coding gene regulatory enhancers are essential to transcription in mammalian cells. As a result, a large variety of experimental and computational strategies have been developed to identify cis-regulatory enhancer sequences. Given the differences in the biological signals assayed, some variation in the enhancers identified by different methods is expected; however, the concordance of enhancers identified by different methods has not been comprehensively evaluated. This is critically needed, since in practice, most studies consider enhancers identified by only a single method. Here, we compare enhancer sets from eleven representative strategies in four biological contexts. Results: All sets we evaluated overlap significantly more than expected by chance; however, there is significant dissimilarity in their genomic, evolutionary, and functional characteristics, both at the element and base-pair level, within each context. The disagreement is sufficient to influence interpretation of candidate SNPs from GWAS studies, and to lead to disparate conclusions about enhancer and disease mechanisms. Most regions identified as enhancers are supported by only one method, and we find limited evidence that regions identified by multiple methods are better candidates than those identified by a single method. As a result, we cannot recommend the use of any single enhancer identification strategy in all settings. Conclusions: Our results highlight the inherent complexity of enhancer biology and identify an important challenge to mapping the genetic architecture of complex disease.