DOCSLIB.ORG

Francine Blumental De Abreu

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

VARIAÇÃO NO NÚMERO DE CÓPIAS GENÔMICAS NA AVALIAÇÃO DE GENES PRINCIPAIS DE PREDISPOSIÇÃO EM PACIENTES COM SÍNDROME DE MAMA-CÓLON TRIADOS PARA MUTAÇÕES NOS GENES BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 FRANCINE BLUMENTAL DE ABREU Tese apresentada à Fundação Antônio Prudente para obtenção do Título de Doutor em Ciências Área de concentração: Oncologia Orientadora: Profª Dra. Silvia Regina Rogatto São Paulo 2012 FICHA CATALOGRÁFICA Preparada pela Biblioteca da Fundação Antônio Prudente Abreu, Francine Blumental de Variação no número de cópias genômicas na avaliação de genes principais de predisposição em pacientes com síndrome de mama- cólon triados para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 E MSH2 / Francine Blumental de Abreu – São Paulo, 2012. 245p. Tese (Doutorado)-Fundação Antônio Prudente. Curso de Pós-Graduação em Ciências - Área de concentração: Oncologia. Orientadora: Silvia Regina Rogatto Descritores: 1. SÍNDROME DE LYNCH. 2. NEOPLASIAS DA MAMA. 3. VARIAÇÃO DO NÚMERO DE CÓPIA DO DNA. 4. HIBRIDIZAÇÃO GENÔMICA COMPARATIVA. DEDICATÓRIA A minha família!!!! AGRADECIMENTOS À minha família... Edilucia (II:5) e Antonio (II:6) por serem mais do que pais, por serem mais do que amigos, por serem os meus super heróis! Obrigada pelos abraços, pelas palavras de apoio e de ensinamento, pelo carinho, pelo amor incondicional! Obrigada por estarem sempre disponíveis, por estenderem as mãos depois de uma “rasteira” da vida, por enxugarem as minhas lágrimas! Obrigada principalmente por me fazerem acreditar que momentos difíceis existem, mas ao lado de vocês, eles se tornam mais fáceis. Obrigada por existirem, obrigada simplesmente por tudo! Obrigada!! Amo vocês!!! Luciana (II:7) pelas palavras de apoio e de ensinamento, pelo carinho e pelo amor!! Obrigada por também estender as mãos depois de uma “rasteira” da vida! Obrigada por fazer parte da minha vida! Obrigada!! Amo você!!! Patrícia (III:5) pelo carinho e pelo amor!! Obrigada por me ouvir! Obrigada pelos conselhos e pelos “puxões de orelha”! Obrigada por cuidar da nossa mãe com tanto carinho e amor! Te amo minha irmã!! Marcelo (III:7) (in memoriam), por estar presente (não de corpo, mas de alma) em todos os momentos da minha vida! Obrigada pelos sonhos!! Obrigada pelo perfume!! Te amo!! Leozinho (III:8) pelos abraços apertados, pelos beijos “do gordo” e pelo brilho nos olhos quando me vê! Obrigada por demonstrar amor e carinho da forma mais sincera e pura! Te amo meu irmãozinho!! Lucy (II:9) e David (II:8) pelo imenso carinho! Obrigada pelas palavras de amigo, ou melhor, pelas palavras de “mãe e pai”! Obrigada pela força e confiança! Amo vocês!! À minha orientadora... Dra Silvia Regina Rogatto pela oportunidade, atenção, preocupação, confiança e ensinamentos durante todos esses anos. Obrigada!! Aos alunos e funcionários do Laboratório Neogene. Obrigada especial aos alunos Fernanda, Hellen e Mateus não só pelos ensinamentos e ajuda na realização desse trabalho, mas também pela amizade! Aos pesquisadores... Dra Ana Krepischi por ter me ajudado nos experimentos e análises de CGH array. Obrigada pelas palavras, abraços, carinho e disponibilidade nos momentos que mais precisei. Obrigada pela confiança! Dr Benedito pela disponibilidade e atenção durante a execução deste trabalho. Obrigada pelo apoio e confiança! Dra Carla Rosemberg pelo conselho e abraço no momento que mais precisei. Muito obrigada! Dra Dirce por disponibilizar seu laboratório, seus alunos e funcionários no auxílio de alguns experimentos. Obrigada pela confiança! Dra Érika pela disponibilidade, atenção e carinho. Obrigada por responder todos os meus e-mails com rapidez e eficiência! Dra Maria Isabel por me ajudar na convocação de pacientes e pela disponibilidade. Obrigada, principalmente, pela confiança! Dr Rafael pela disponibilidade e atenção durante os momentos finais da tese. Obrigada! Agradecimento especial à Dra Ana Krepischi, Dra Dirce, Dr Fernando e Dra Maria Isabel por confiarem em mim e por me ajudarem na realização de um sonho! Obrigada do fundo meu coração!! Aos meus amigos... “E o que importa não é o que você tem na vida, mas quem você tem na vida. E que bons amigos são a família que nos permitiram escolher” (autor desconhecido) Elô e Carol por serem mais do que amigas irmãs! Obrigada pelos queijos e vinhos, cervejas, piadas, conselhos, baladas, filmes....obrigada por me fazerem chorar de tanto rir....obrigada por enxugarem as minhas lágrimas....obrigada por existirem e fazerem parte da minha vida!!! Amo vocês! Eliane, Renata e Fabíola por estarem perto mesmo estando longe! Obrigada pelos e-mails, telefonemas, mensagens, visitas! Obrigada pelos ensinamentos!! Obrigada pelo carinho!! Amo vocês! Tati e Amanda pelo carinho, pelos conselhos e abraços! Obrigada por segurarem minhas mãos nos momentos mais difíceis! Obrigada pelos “puxões de orelha”! Obrigada por me fazerem sorrir!! Amo vocês! Aos alunos e funcionários do laboratório LGBM... Bianca, Bruna, Cris, Dani, Elisa, Felipe, Gi e Márcia, pela disponibilidade em me ajudar na execução de alguns experimentos. Obrigada principalmente pelo carinho, pelos fortes abraços, pelos conselhos!!! Vocês são pessoas muito especiais!! Ao hospital AC Camargo... Funcionários do Banco de Macromoléculas (Ana, Eloisa e Louise) pela ajuda na aquisição das amostras e ajuda na pesquisa de amostras. Obrigada especial a Ana e Eloisa por estarem do meu lado como amigas! Funcionários da Biblioteca (Jefferson e Sueli) pelo auxílio durante as pesquisas bibliográficas, pesquisa de artigos científicos e revisão deste trabalho. Obrigada pelo carinho com que me trataram todos esses anos! Funcionárias da Pós-graduação (Ana, Luciana e Vanusa) pelo auxílio oferecido no decorrer desses anos. Funcionários do SAME por separar os prontuários dos pacientes dessa pesquisa. As Instituições de Fomento... FAPESP e CNPq pelo suporte financeiro. O valor das coisas não está no tempo que elas duram, mas na intensidade com que acontecem. Por isso existem momentos inesquecíveis, coisas inexplicáveis e pessoas incomparáveis. (Fernando Pessoa) RESUMO Abreu FB. Variação no número de cópias genômicas na avaliação de genes principais de predisposição em pacientes com Síndrome de Mama-Cólon triados para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 e MSH2. São Paulo; 2012. [Tese de Doutorado-Fundação Antônio Prudente]. A Síndrome de Lynch (SL) é uma síndrome hereditária de predisposição ao câncer colorretal associado com um risco aumentado de desenvolvimento de tumores extracolônicos. No Brasil, o carcinoma mamário é o tumor extracolônico de maior inciência na SL. Neste estudo, 65 pacientes foram divididos em três grupos: 1 e 2, composto por 59 pacientes negativos para mutações nos genes BRCA1, BRCA2, TP53, CHEK2, MLH1 e MSH2 e, 3, formado por 6 pacientes com mutação em um desses genes. O grupo 1 apresentava 26 pacientes com câncer de mama ou colorretal, grupo 2 apresentava 33 pacientes com câncer de mama e colorretal. As variações no número de cópias genômicas (CNVs) foram investigadas pelo método de CGH array utilizando a plataforma de 4x180K (Agilent Techonologies). Os dados foram extraídos no Software Feature Extraction e analisados no Software Genomic Workbench 5.0. Para a análise foram utilizados o algoritmo estatístico ADM-2, threshold 6,7 e -0,3≤log2≥0,3 para determinar as regiões de ganhos e perdas genômicas. As alterações foram comparadas com o banco de dados DGV e com um banco de dados específico da população brasileira (grupo referência). Na análise de aCGH, foram identificadas 451 alterações, sendo 161 do grupo 1, 257 do grupo 2 e 33 do grupo 3. Após a comparação com o banco de dados da população brasileira, as alterações foram classificadas em comuns, raras e novas raras. Foram consideradas como relevantes para o estudo apenas as CNVs raras, identificadas em 1% da população de referência, e as CNVs novas raras, ausentes tanto na população de referência como no banco de dados DGV. Entre os pacientes sem mutação, foram identificadas CVNs novas raras comuns e exclusivas aos grupo 1 e 2. O gene SLC38A6 foi identificado em duas pacientes do grupo 1 e uma do grupo 2. É um gene envolvido no transporte de glutamina, um aminoácido envolvido em muitas funções, entre elas produção de ATP. Os genes envolvidos em ganho genômico, GRM1 e TMPRSS3 (exclusivos do grupo 1) e FOXP1 e BLM (exclusivos do grupo 2) têm potencial para contribuir para o desenvolvimento tumoral. Na análise familial, foram identificados genes e microRNA envolvidos em CNVs raras e novas raras com potencial para o desenvolvimento e predisposição ao câncer de mama e colorretal. A perda genômica no gene ROBO1 foi identificada em duas pacientes (grupo 1 e 2) e em seus respectivos familiares. Essa alteração foi confirmada por qPCR e a baixa expressão da proteína ROBO1 foi associada com pior prognóstico da doença. Os resultados sugerem que determinadas alterações genômicas tem potencial associação com a predisposição hereditária tumores de mama e colorretal. SUMMARY Abreu FB. [Analysis of copy number alterations in patients with breast and colorectal cancer syndrome that are negative for BRCA1, BRCA2, TP53, CHEK2, MLH1 and MSH2 mutations]. São Paulo, 2012. [Tese de Doutorado-Fundação Antônio Prudente]. Lynch syndrome (LS) is a hereditary colorectal cancer syndrome associated to an increased risk to develop extracolonic tumors. In Brazil, breast cancer is the extracolonic tumor with more incidence among LS patients. On this study, 65 patients were dividided into three groups: 1 and 2, composed of 59 patients negative for BRCA1, BRCA2, TP53, CHEK2, MLH1 and MSH2 mutations and, 3, composed of six patients with a mutation in one of these genes. Group 1 had 26 patients with breast or colorectal cancer and group 2 had 33 patients with breast and colorectal cancer. Copy number variations (CNVs) were investigated by CGH array using 4x180K platform (Agilent Techonologies). Data were extracted by Feature Extraction Software and analyzed by Genomic Workbench 5.0 Software, using the ADM2 algorithm with a 6.7 threshold and absolute log ratio filter of -0,3≤log2≥0,3 to identify genomic losses and gains.
Recommended publications
  • Isyte: Integrated Systems Tool for Eye Gene Discovery

    Isyte: Integrated Systems Tool for Eye Gene Discovery

    Lens iSyTE: Integrated Systems Tool for Eye Gene Discovery Salil A. Lachke,1,2,3,4 Joshua W. K. Ho,1,4,5 Gregory V. Kryukov,1,4,6 Daniel J. O’Connell,1 Anton Aboukhalil,1,7 Martha L. Bulyk,1,8,9 Peter J. Park,1,5,10 and Richard L. Maas1 PURPOSE. To facilitate the identification of genes associated ther investigation. Extension of this approach to other ocular with cataract and other ocular defects, the authors developed tissue components will facilitate eye disease gene discovery. and validated a computational tool termed iSyTE (integrated (Invest Ophthalmol Vis Sci. 2012;53:1617–1627) DOI: Systems Tool for Eye gene discovery; http://bioinformatics. 10.1167/iovs.11-8839 udel.edu/Research/iSyTE). iSyTE uses a mouse embryonic lens gene expression data set as a bioinformatics filter to select candidate genes from human or mouse genomic regions impli- ven with the advent of high-throughput sequencing, the cated in disease and to prioritize them for further mutational Ediscovery of genes associated with congenital birth defects and functional analyses. such as eye defects remains a challenge. We sought to develop METHODS. Microarray gene expression profiles were obtained a straightforward experimental approach that could facilitate for microdissected embryonic mouse lens at three key devel- the identification of candidate genes for developmental disor- opmental time points in the transition from the embryonic day ders, and, as proof-of-principle, we chose defects involving the (E)10.5 stage of lens placode invagination to E12.5 lens primary ocular lens. Opacification of the lens results in cataract, a leading cause of blindness that affects 77 million persons and fiber cell differentiation.
  • Association Analyses of Known Genetic Variants with Gene

    Association Analyses of Known Genetic Variants with Gene

    ASSOCIATION ANALYSES OF KNOWN GENETIC VARIANTS WITH GENE EXPRESSION IN BRAIN by Viktoriya Strumba A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Bioinformatics) in The University of Michigan 2009 Doctoral Committee: Professor Margit Burmeister, Chair Professor Huda Akil Professor Brian D. Athey Assistant Professor Zhaohui S. Qin Research Statistician Thomas Blackwell To Sam and Valentina Dmitriy and Elizabeth ii ACKNOWLEDGEMENTS I would like to thank my advisor Professor Margit Burmeister, who tirelessly guided me though seemingly impassable corridors of graduate work. Throughout my thesis writing period she provided sound advice, encouragement and inspiration. Leading by example, her enthusiasm and dedication have been instrumental in my path to becoming a better scientist. I also would like to thank my co-advisor Tom Blackwell. His careful prodding always kept me on my toes and looking for answers, which taught me the depth of careful statistical analysis. His diligence and dedication have been irreplaceable in most difficult of projects. I also would like to thank my other committee members: Huda Akil, Brian Athey and Steve Qin as well as David States. You did not make it easy for me, but I thank you for believing and not giving up. Huda’s eloquence in every subject matter she explained have been particularly inspiring, while both Huda’s and Brian’s valuable advice made the completion of this dissertation possible. I would also like to thank all the members of the Burmeister lab, both past and present: Sandra Villafuerte, Kristine Ito, Cindy Schoen, Karen Majczenko, Ellen Schmidt, Randi Burns, Gang Su, Nan Xiang and Ana Progovac.
  • Systems and Chemical Biology Approaches to Study Cell Function and Response to Toxins

    Systems and Chemical Biology Approaches to Study Cell Function and Response to Toxins

    Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences Presented by MSc. Yingying Jiang born in Shandong, China Oral-examination: Systems and chemical biology approaches to study cell function and response to toxins Referees: Prof. Dr. Rob Russell Prof. Dr. Stefan Wölfl CONTRIBUTIONS The chapter III of this thesis was submitted for publishing under the title “Drug mechanism predominates over toxicity mechanisms in drug induced gene expression” by Yingying Jiang, Tobias C. Fuchs, Kristina Erdeljan, Bojana Lazerevic, Philip Hewitt, Gordana Apic & Robert B. Russell. For chapter III, text phrases, selected tables, figures are based on this submitted manuscript that has been originally written by myself. i ABSTRACT Toxicity is one of the main causes of failure during drug discovery, and of withdrawal once drugs reached the market. Prediction of potential toxicities in the early stage of drug development has thus become of great interest to reduce such costly failures. Since toxicity results from chemical perturbation of biological systems, we combined biological and chemical strategies to help understand and ultimately predict drug toxicities. First, we proposed a systematic strategy to predict and understand the mechanistic interpretation of drug toxicities based on chemical fragments. Fragments frequently found in chemicals with certain toxicities were defined as structural alerts for use in prediction. Some of the predictions were supported with mechanistic interpretation by integrating fragment- chemical, chemical-protein, protein-protein interactions and gene expression data. Next, we systematically deciphered the mechanisms of drug actions and toxicities by analyzing the associations of drugs’ chemical features, biological features and their gene expression profiles from the TG-GATEs database.
  • Two Locus Inheritance of Non-Syndromic Midline Craniosynostosis Via Rare SMAD6 and 4 Common BMP2 Alleles 5 6 Andrew T

    Two Locus Inheritance of Non-Syndromic Midline Craniosynostosis Via Rare SMAD6 and 4 Common BMP2 Alleles 5 6 Andrew T

    1 2 3 Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and 4 common BMP2 alleles 5 6 Andrew T. Timberlake1-3, Jungmin Choi1,2, Samir Zaidi1,2, Qiongshi Lu4, Carol Nelson- 7 Williams1,2, Eric D. Brooks3, Kaya Bilguvar1,5, Irina Tikhonova5, Shrikant Mane1,5, Jenny F. 8 Yang3, Rajendra Sawh-Martinez3, Sarah Persing3, Elizabeth G. Zellner3, Erin Loring1,2,5, Carolyn 9 Chuang3, Amy Galm6, Peter W. Hashim3, Derek M. Steinbacher3, Michael L. DiLuna7, Charles 10 C. Duncan7, Kevin A. Pelphrey8, Hongyu Zhao4, John A. Persing3, Richard P. Lifton1,2,5,9 11 12 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 13 2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA 14 3Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT, USA 15 4Department of Biostatistics, Yale University School of Medicine, New Haven, CT, USA 16 5Yale Center for Genome Analysis, New Haven, CT, USA 17 6Craniosynostosis and Positional Plagiocephaly Support, New York, NY, USA 18 7Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA 19 8Child Study Center, Yale University School of Medicine, New Haven, CT, USA 20 9The Rockefeller University, New York, NY, USA 21 22 ABSTRACT 23 Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2,000 24 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To 25 identify mutations contributing to common non-syndromic midline (sagittal and metopic) 26 craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 27 additional probands.
  • Manual Annotation and Analysis of the Defensin Gene Cluster in the C57BL

    Manual Annotation and Analysis of the Defensin Gene Cluster in the C57BL

    BMC Genomics BioMed Central Research article Open Access Manual annotation and analysis of the defensin gene cluster in the C57BL/6J mouse reference genome Clara Amid*†1, Linda M Rehaume*†2, Kelly L Brown2,3, James GR Gilbert1, Gordon Dougan1, Robert EW Hancock2 and Jennifer L Harrow1 Address: 1Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK, 2University of British Columbia, Centre for Microbial Disease & Immunity Research, 2259 Lower Mall, Vancouver, BC, V6T 1Z4, Canada and 3Department of Rheumatology and Inflammation Research, Göteborg University, Guldhedsgatan 10, S-413 46 Göteborg, Sweden Email: Clara Amid* - [email protected]; Linda M Rehaume* - [email protected]; Kelly L Brown - [email protected]; James GR Gilbert - [email protected]; Gordon Dougan - [email protected]; Robert EW Hancock - [email protected]; Jennifer L Harrow - [email protected] * Corresponding authors †Equal contributors Published: 15 December 2009 Received: 15 May 2009 Accepted: 15 December 2009 BMC Genomics 2009, 10:606 doi:10.1186/1471-2164-10-606 This article is available from: http://www.biomedcentral.com/1471-2164/10/606 © 2009 Amid et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Host defense peptides are a critical component of the innate immune system. Human alpha- and beta-defensin genes are subject to copy number variation (CNV) and historically the organization of mouse alpha-defensin genes has been poorly defined.
  • Genome-Wide Association Analysis on Coronary Artery Disease in Type 1 Diabetes Suggests Beta-Defensin 127 As a Novel Risk Locus

    Genome-Wide Association Analysis on Coronary Artery Disease in Type 1 Diabetes Suggests Beta-Defensin 127 As a Novel Risk Locus

    Genome-wide association analysis on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a novel risk locus Antikainen, A., Sandholm, N., Tregouet, D-A., Charmet, R., McKnight, A., Ahluwalia, T. V. S., Syreeni, A., Valo, E., Forsblom, C., Gordin, D., Harjutsalo, V., Hadjadj, S., Maxwell, P., Rossing, P., & Groop, P-H. (2020). Genome-wide association analysis on coronary artery disease in type 1 diabetes suggests beta-defensin 127 as a novel risk locus. Cardiovascular Research. https://doi.org/10.1093/cvr/cvaa045 Published in: Cardiovascular Research Document Version: Peer reviewed version Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal Publisher rights Copyright 2020 OUP. This work is made available online in accordance with the publisher’s policies. Please refer to any applicable terms of use of the publisher. General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact [email protected]. Download date:01. Oct.
  • Molecular Characterization of Latent GDF8 Reveals Mechanisms

    Molecular Characterization of Latent GDF8 Reveals Mechanisms

    Molecular characterization of latent GDF8 reveals PNAS PLUS mechanisms of activation Ryan G. Walkera,1, Jason C. McCoya,1, Magdalena Czepnika, Melanie J. Millsb,c, Adam Haggd,e, Kelly L. Waltond, Thomas R. Cottonf, Marko Hyvönenf, Richard T. Leeb,c, Paul Gregorevice,g,h,i, Craig A. Harrisond,j,2, and Thomas B. Thompsona,2 aDepartment of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267; bHarvard Stem Cell Institute, Harvard University, Cambridge, MA 02138; cDepartment of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; dBiomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, VIC 3800, Australia; eBaker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; fDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom; gDepartment of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; hDepartment of Physiology, University of Melbourne, Parkville, VIC 3010, Australia; iDepartment of Neurology, University of Washington School of Medicine, Seattle, WA 98195; and jHudson Institute of Medical Research, Clayton, VIC 3168, Australia Edited by Se-Jin Lee, Johns Hopkins University, Baltimore, MD, and approved December 7, 2017 (received for review August 22, 2017) Growth/differentiation factor 8 (GDF8), or myostatin, negatively the latent TGF-β1 crystal structure provided a molecular expla- regulates muscle mass. GDF8 is held in a latent state through nation for how latency is exerted by the prodomain via a co- interactions with its N-terminal prodomain, much like TGF-β. Using ordinated interaction between the N-terminal alpha helix (alpha- a combination of small-angle X-ray scattering and mutagenesis, 1), latency lasso, and fastener of the prodomain with type I and we characterized the interactions of GDF8 with its prodomain.
  • Revealing the Role of the Human Blood Plasma Proteome in Obesity Using Genetic Drivers

    Revealing the Role of the Human Blood Plasma Proteome in Obesity Using Genetic Drivers

    ARTICLE https://doi.org/10.1038/s41467-021-21542-4 OPEN Revealing the role of the human blood plasma proteome in obesity using genetic drivers Shaza B. Zaghlool 1,11, Sapna Sharma2,3,4,11, Megan Molnar 2,3, Pamela R. Matías-García2,3,5, Mohamed A. Elhadad 2,3,6, Melanie Waldenberger 2,3,7, Annette Peters 3,4,7, Wolfgang Rathmann4,8, ✉ Johannes Graumann 9,10, Christian Gieger2,3,4, Harald Grallert2,3,4,12 & Karsten Suhre 1,12 Blood circulating proteins are confounded readouts of the biological processes that occur in 1234567890():,; different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets fur- ther elucidating the role of these proteins in obesity associated pathologies. 1 Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.
  • Mapping DNA Structural Variation in Dogs

    Mapping DNA Structural Variation in Dogs

    Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Resource Mapping DNA structural variation in dogs Wei-Kang Chen,1,4 Joshua D. Swartz,1,4,5 Laura J. Rush,2 and Carlos E. Alvarez1,3,6 1Center for Molecular and Human Genetics, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, USA; 2Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, USA; 3Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA DNA structural variation (SV) comprises a major portion of genetic diversity, but its biological impact is unclear. We propose that the genetic history and extraordinary phenotypic variation of dogs make them an ideal mammal in which to study the effects of SV on biology and disease. The hundreds of existing dog breeds were created by selection of extreme morphological and behavioral traits. And along with those traits, each breed carries increased risk for different diseases. We used array CGH to create the first map of DNA copy number variation (CNV) or SV in dogs. The extent of this variation, and some of the gene classes affected, are similar to those of mice and humans. Most canine CNVs affect genes, including disease and candidate disease genes, and are thus likely to be functional. We identified many CNVs that may be breed or breed class specific. Cluster analysis of CNV regions showed that dog breeds tend to group according to breed classes. Our combined findings suggest many CNVs are (1) in linkage disequilibrium with flanking sequence, and (2) associated with breed-specific traits.
  • Download The

    Download The

    PROBING THE INTERACTION OF ASPERGILLUS FUMIGATUS CONIDIA AND HUMAN AIRWAY EPITHELIAL CELLS BY TRANSCRIPTIONAL PROFILING IN BOTH SPECIES by POL GOMEZ B.Sc., The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2010 © Pol Gomez, 2010 ABSTRACT The cells of the airway epithelium play critical roles in host defense to inhaled irritants, and in asthma pathogenesis. These cells are constantly exposed to environmental factors, including the conidia of the ubiquitous mould Aspergillus fumigatus, which are small enough to reach the alveoli. A. fumigatus is associated with a spectrum of diseases ranging from asthma and allergic bronchopulmonary aspergillosis to aspergilloma and invasive aspergillosis. Airway epithelial cells have been shown to internalize A. fumigatus conidia in vitro, but the implications of this process for pathogenesis remain unclear. We have developed a cell culture model for this interaction using the human bronchial epithelium cell line 16HBE and a transgenic A. fumigatus strain expressing green fluorescent protein (GFP). Immunofluorescent staining and nystatin protection assays indicated that cells internalized upwards of 50% of bound conidia. Using fluorescence-activated cell sorting (FACS), cells directly interacting with conidia and cells not associated with any conidia were sorted into separate samples, with an overall accuracy of 75%. Genome-wide transcriptional profiling using microarrays revealed significant responses of 16HBE cells and conidia to each other. Significant changes in gene expression were identified between cells and conidia incubated alone versus together, as well as between GFP positive and negative sorted cells.
  • Cellular and Molecular Signatures in the Disease Tissue of Early

    Cellular and Molecular Signatures in the Disease Tissue of Early

    Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of
  • Role of Amylase in Ovarian Cancer Mai Mohamed University of South Florida, Mmohamed@Health.Usf.Edu

    Role of Amylase in Ovarian Cancer Mai Mohamed University of South Florida, [email protected]

    University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School July 2017 Role of Amylase in Ovarian Cancer Mai Mohamed University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Pathology Commons Scholar Commons Citation Mohamed, Mai, "Role of Amylase in Ovarian Cancer" (2017). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/6907 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Role of Amylase in Ovarian Cancer by Mai Mohamed A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Pathology and Cell Biology Morsani College of Medicine University of South Florida Major Professor: Patricia Kruk, Ph.D. Paula C. Bickford, Ph.D. Meera Nanjundan, Ph.D. Marzenna Wiranowska, Ph.D. Lauri Wright, Ph.D. Date of Approval: June 29, 2017 Keywords: ovarian cancer, amylase, computational analyses, glycocalyx, cellular invasion Copyright © 2017, Mai Mohamed Dedication This dissertation is dedicated to my parents, Ahmed and Fatma, who have always stressed the importance of education, and, throughout my education, have been my strongest source of encouragement and support. They always believed in me and I am eternally grateful to them. I would also like to thank my brothers, Mohamed and Hussien, and my sister, Mariam. I would also like to thank my husband, Ahmed.