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A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Lane, Jérôme ; McLaren, Paul J. ; Dorrell, Lucy ; Shianna, Kevin V. ; Stemke, Amanda ; Pelak, Kimberly ; Moore, Stephen ; Oldenburg, Johannes ; Alvarez-Roman, Maria Teresa ; Angelillo-Scherrer, Anne ; Boehlen, Francoise ; Bolton-Maggs, Paula H.B. ; Brand, Brigit ; Brown, Deborah ; Chiang, Elaine ; Cid-Haro, Ana Rosa ; Clotet, Bonaventura ; Collins, Peter ; Colombo, Sara ; Dalmau, Judith ; Fogarty, Patrick ; Giangrande, Paul ; Gringeri, Alessandro ; Iyer, Rathi ; Katsarou, Olga ; Kempton, Christine ; Kuriakose, Philip ; Lin, Judith ; Makris, Mike ; Manco-Johnson, Marilyn ; Tsakiris, Dimitrios A. ; Martinez-Picado, Javier ; Mauser-Bunschoten, Evelien ; Neff, Anne ; Oka, Shinichi ; Oyesiku, Lara ; Parra, Rafael ; Peter-Salonen, Kristiina ; Powell, Jerry ; Recht, Michael ; Shapiro, Amy ; Stine, Kimo ; Talks, Katherine ; Telenti, Amalio ; Wilde, Jonathan ; Yee, Thynn Thynn ; Wolinsky, Steven M. ; Martinson, Jeremy ; Hussain, Shehnaz K. ; Bream, Jay H. ; Jacobson, Lisa P. ; Carrington, Mary ; Goedert, James J. ; Haynes, Barton F. ; McMichael, Andrew J. ; Goldstein, David B. ; Fellay, Jacques

In: Human Molecular Genetics, 2013, vol. 22, no. 9, p. 1903-1910

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    Titre
    • A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A
    Auteur
    • Lane, Jérôme. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    • McLaren, Paul J.. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    • Dorrell, Lucy. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
    • Shianna, Kevin V.. Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA
    • Stemke, Amanda. Duke Human Vaccine Institute, Duke University, Durham, NC, USA
    • Pelak, Kimberly. Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA
    • Moore, Stephen. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
    • Oldenburg, Johannes. Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
    • Alvarez-Roman, Maria Teresa. Unidad de Coagulopatias Congenitas, La Paz University Hospital, Madrid, Spain
    • Angelillo-Scherrer, Anne. Service and Central Laboratory of Hematology, Lausanne University Hospital, Lausanne, Switzerland
    • Boehlen, Francoise. Division of Angiology and Haemostasis, Department of Specialties of Medicine, University Hospitals, Geneva, Switzerland
    • Bolton-Maggs, Paula H.B.. Manchester Haemophilia Comprehensive Care Centre, Manchester Royal Infirmary, University of Manchester, Manchester, UK
    • Brand, Brigit. Division of Hematology, University Hospital, Zurich, Switzerland
    • Brown, Deborah. Gulf States Hemophilia and Thrombophilia Center, Houston, TX, USA
    • Chiang, Elaine. University of Pennsylvania, Penn Comprehensive Hemophilia and Thrombosis Program, Philadelphia, PA, USA
    • Cid-Haro, Ana Rosa. Unidad de Coagulopatias Congenitas, La Fe University Hospital, Valencia, Spain
    • Clotet, Bonaventura. AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
    • Collins, Peter. Arthur Bloom Haemophilia Centre, School of Medicine, Cardiff University, Wales, UK
    • Colombo, Sara. Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Dalmau, Judith. AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
    • Fogarty, Patrick. University of California San Francisco, San Francisco, CA, USA
    • Giangrande, Paul. Oxford Haemophilia and Thrombosis Centre, Oxford University Hospitals NHS Trust, Oxford, UK
    • Gringeri, Alessandro. Università degli Studi di Milano and Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milan, Italy
    • Iyer, Rathi. UMHC Clinic for Bleeding and Clotting Disorders, University of Mississippi Medical Center, Jackson, MS, USA
    • Katsarou, Olga. Blood Centre and National Reference Centre for Congenital Bleeding Disorders, Laiko General Hospital, Athens, Greece
    • Kempton, Christine. Adult Hemophilia Program, Emory University, Atlanta, GA, USA
    • Kuriakose, Philip. Henry Ford Health System, Detroit, MI, USA
    • Lin, Judith. Boston Hemophilia Center, Brigham and Women's Hospital, Boston, MA, USA
    • Makris, Mike. Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
    • Manco-Johnson, Marilyn. Department of Pediatrics, University of Colorado and Children's Hospital Colorado, Aurora, USA
    • Tsakiris, Dimitrios A.. Hemophilia Comprehensive Care Center, University Hospital, Basel, Switzerland
    • Martinez-Picado, Javier. AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
    • Mauser-Bunschoten, Evelien. University Medical Center Utrecht, Utrecht, Netherlands
    • Neff, Anne. Hemostasis-Thrombosis Clinic, Vanderbilt University, Nashville, TN, USA
    • Oka, Shinichi. National Center for Global Health and Medicine, Tokyo, Japan
    • Oyesiku, Lara. Oxford Haemophilia and Thrombosis Centre, Oxford University Hospitals NHS Trust, Oxford, UK
    • Parra, Rafael. Hemophilia Unit, Hospital Vall d'Hebron, Barcelona, Spain
    • Peter-Salonen, Kristiina. Hematology, Inselspital, University Hospital Bern, Bern, Switzerland
    • Powell, Jerry. UC Davis Hemophilia Treatment Center, Sacramento, CA, USA
    • Recht, Michael. The Hemophilia Center, Oregon Health & Science University, Portland, OR, USA
    • Shapiro, Amy. Indiana Hemophilia & Thrombosis Center, Indianapolis, IN, USA
    • Stine, Kimo. Hemophilia Treatment Center of Arkansas, Arkansas Children's Hospital, Little Rock, AR, USA
    • Talks, Katherine. Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
    • Telenti, Amalio. Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Wilde, Jonathan. New Queen Elizabeth Hospital, Edgbaston, Birmingham, UK
    • Yee, Thynn Thynn. Katharine Dormandy Haemophilia Centre & Thrombosis Unit, Royal Free Hospital, London, UK
    • Wolinsky, Steven M.. Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
    • Martinson, Jeremy. Department of Pathology, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
    • Hussain, Shehnaz K.. Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USA
    • Bream, Jay H.. Department of Molecular Microbiology and Immunology and
    • Jacobson, Lisa P.. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    • Carrington, Mary. Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC Frederick, Inc., Frederick National Lab, Frederick, MD, USA
    • Goedert, James J.. Division of Cancer Epidemiology and Genetics, NCI, Bethesda, MD, USA
    • Haynes, Barton F.. Duke Human Vaccine Institute, Duke University, Durham, NC, USA
    • McMichael, Andrew J.. Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
    • Goldstein, David B.. Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA
    • Fellay, Jacques. School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Human Molecular Genetics, 2013, vol. 22, no. 9, p. 1903-1910. Oxford University Press
    Autre version électronique
    Classification
    • Santé
    Identifiant OAI-PMH
    • oai:doc.rero.ch:295513
    Summary
    Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population