Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls

PLoS Pathogens

Ioannis Theodorou¹  David Haas²  Pierre Rucart²  Susan Buchbinder³  Patrick R. Shea³  Stephen J. O'Brien⁴  Steven G. Deeks⁵  Olivier Delaneau⁶  Jean-François Zagury⁶  Laurence Meyer⁷  Andrea Cossarizza⁸  José M. Miro⁹  Ying Qi^1,10  Bruce D. Walker^1,11  Amalio Telenti^1,12  Florencia Pereyra^1,12  Joshua T. Herbeck^1,13  Jan Veldink^1,14  Daniëlle van Manen^1,14  Judith Dalmau^1,15  Sekar Kathiresan^1,16  James J. Goedert^1,17  Paul I. W. de Bakker^1,18  Steven Wolinsky^1,19  James I. Mullins^2,20  Ma Luo^2,21  Fredrik Vannberg^2,22  Hanneke Schuitemaker^2,23  Manj S. Sandhu^2,24  Guido Poli^2,25  Olivier Lambotte^2,26  Cédric Coulonges^2,27  Leonard van den Berg^2,28  Jacques Fellay^2,28  Francis A. Plummer^2,29  David B. Goldstein^2,29  Stephan Ripke^3,30  Javier Martinez-Picado^3,30  Mary Carrington^3,30  Andrea De Luca^3,31  Cheryl A. Winkler^3,31  Paul J. McLaren^3,32  Amy Weintrob^3,33  Gregory D. Kirk^3,34  Niels Obel^3,35  Simon Mallal^3,36 

[1] AP-HP, Hopital Bicêtre, Epidemiology and Public Health Service, Le Kremlin Bicêtre, France;AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain;ANRS Genomic Group (French Agency for Research on AIDS and Hepatitis), Paris, France;AP-HP, Department of Internal Medicine and Infectious Diseases, Bicêtre Hospital, Bicêtre, France;Bridge HIV, San Francisco Department of Public Health, San Francisco, California, United States of America;Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America;Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, United States of America;Department of Experimental Immunology, Sanquin Research, Landsteiner Laboratory, and Center for Infectious Diseases and Immunity Amsterdam (CINIMA) at the Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands;Department of Infectious Diseases, The National University Hospital, Rigshospitalet, Copenhagen, Denmark;Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada;Department of Medicine, University of California, San Francisco, California, United States of America;Department of Microbiology, University of Washington, Seattle, Washington, United States of America;Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands;Department of Statistics, University of Oxford, Oxford, United Kingdom;Department of Surgery, Medicine, Dentistry and Morphological Sciences University of Modena and Reggio Emilia School of Medicine, Modena, Italy;Division of Immunology, Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, School of Medicine & San Raffaele Scientific Institute, Milan, Italy;Division of Infectious Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;INSERM U1012, Bicêtre, France;Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America;Infectious Diseases Service. Hospital Clinic – IDIBAPS, University of Barcelona, Barcelona, Spain;Inserm, CESP U1018, University Paris-Sud, UMRS 1018, Faculté de Médecine Paris-Sud;Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain;Institute for Immunology & Infectious Diseases, Murdoch University and Pathwest, Perth, Australia;Institute of Clinical infectious Diseases, Università Cattolica del Sacro Cuore, Roma, Italy;Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland;Laboratoire Génomique, Bioinformatique, et Applications, EA4627, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France;National Microbiology Laboratory, Winnipeg, Manitoba, Canada;Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America;Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, United States of America;School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland;Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russia;University Division of Infectious Diseases, Siena University Hospital, Siena, Italy;University Paris-Sud, Bicêtre, France;Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America

关键词: HIV-1;    Genome-wide association studies;    HIV;    Molecular genetics;    Genetics of disease;    Europe;    Variant genotypes;    Infectious disease control;   

DOI  :  10.1371/journal.ppat.1003515

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

【 授权许可】

CC BY