Ping An1, James J Goedert2, Sharyne Donfield3, Susan Buchbinder4, Gregory D Kirk5, Roger Detels6, Cheryl A Winkler1. 1. Basic Research Laboratory, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research. 2. Infections and Immunoepidemology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 3. Rho, Inc, Chapel Hill, North Carolina. 4. San Francisco Department of Public Health, California. 5. Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland. 6. Department of Epidemiology, School of Public Health, University of California, Los Angeles.
Abstract
BACKGROUND: ZNRD1 was identified as a host protein required for the completion of the human immunodeficiency virus (HIV) lifecycle in a genome-wide screen using small interfering RNA gene silencing. Subsequently, a genome-wide association study (GWAS) of host determinants for HIV-1 disease identified an association of single nucleotide polymorphisms (SNPs) in the ZNRD1 region with CD4(+) T-cell depletion. METHODS: We investigated the effects of SNPs in the ZNRD1 region on human immunodeficiency virus type 1 (HIV-1) infection and progression to clinical outcomes in 5 US-based HIV-1 longitudinal cohorts consisting of men who have sex with men, males with hemophilia, and injection drug users (IDUs) (n = 1865). SNP function was evaluated by electrophoretic mobility shift assay and promoter luciferase assay. RESULTS: A haplotype in the ZNRD1 gene showed significant association with a 35% decreased risk of HIV-1 acquisition (OR = 0.65, 95% CI, .47-.89), independent of HLA-C rs9264942, in European Americans. The SNP rs3132130 tagging this haplotype, located in the ZNRD1 5' upstream region, caused a loss of nuclear factor binding and decrease in ZNRD1 promoter activity. ZNRD1 variants also affected HIV-1 disease progression in European- and African-American cohorts. CONCLUSIONS: This study provides novel evidence that ZNRD1 polymorphism may confer host resistance to HIV-1 acquisition. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
BACKGROUND:ZNRD1 was identified as a host protein required for the completion of the human immunodeficiency virus (HIV) lifecycle in a genome-wide screen using small interfering RNA gene silencing. Subsequently, a genome-wide association study (GWAS) of host determinants for HIV-1 disease identified an association of single nucleotide polymorphisms (SNPs) in the ZNRD1 region with CD4(+) T-cell depletion. METHODS: We investigated the effects of SNPs in the ZNRD1 region on human immunodeficiency virus type 1 (HIV-1) infection and progression to clinical outcomes in 5 US-based HIV-1 longitudinal cohorts consisting of men who have sex with men, males with hemophilia, and injection drug users (IDUs) (n = 1865). SNP function was evaluated by electrophoretic mobility shift assay and promoter luciferase assay. RESULTS: A haplotype in the ZNRD1 gene showed significant association with a 35% decreased risk of HIV-1 acquisition (OR = 0.65, 95% CI, .47-.89), independent of HLA-C rs9264942, in European Americans. The SNP rs3132130 tagging this haplotype, located in the ZNRD1 5' upstream region, caused a loss of nuclear factor binding and decrease in ZNRD1 promoter activity. ZNRD1 variants also affected HIV-1 disease progression in European- and African-American cohorts. CONCLUSIONS: This study provides novel evidence that ZNRD1 polymorphism may confer host resistance to HIV-1 acquisition. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Authors: Daniëlle van Manen; Neeltje A Kootstra; Brigitte Boeser-Nunnink; Muna Am Handulle; Angélique B van't Wout; Hanneke Schuitemaker Journal: AIDS Date: 2009-01-02 Impact factor: 4.177
Authors: Rasmi Thomas; Richard Apps; Ying Qi; Xiaojiang Gao; Victoria Male; Colm O'hUigin; Geraldine O'Connor; Dongliang Ge; Jacques Fellay; Jeffrey N Martin; Joseph Margolick; James J Goedert; Susan Buchbinder; Gregory D Kirk; Maureen P Martin; Amalio Telenti; Steven G Deeks; Bruce D Walker; David Goldstein; Daniel W McVicar; Ashley Moffett; Mary Carrington Journal: Nat Genet Date: 2009-12 Impact factor: 38.330
Authors: Abraham L Brass; Derek M Dykxhoorn; Yair Benita; Nan Yan; Alan Engelman; Ramnik J Xavier; Judy Lieberman; Stephen J Elledge Journal: Science Date: 2008-01-10 Impact factor: 47.728
Authors: Jacques Fellay; Dongliang Ge; Kevin V Shianna; Sara Colombo; Bruno Ledergerber; Elizabeth T Cirulli; Thomas J Urban; Kunlin Zhang; Curtis E Gumbs; Jason P Smith; Antonella Castagna; Alessandro Cozzi-Lepri; Andrea De Luca; Philippa Easterbrook; Huldrych F Günthard; Simon Mallal; Cristina Mussini; Judith Dalmau; Javier Martinez-Picado; José M Miro; Niels Obel; Steven M Wolinsky; Jeremy J Martinson; Roger Detels; Joseph B Margolick; Lisa P Jacobson; Patrick Descombes; Stylianos E Antonarakis; Jacques S Beckmann; Stephen J O'Brien; Norman L Letvin; Andrew J McMichael; Barton F Haynes; Mary Carrington; Sheng Feng; Amalio Telenti; David B Goldstein Journal: PLoS Genet Date: 2009-12-24 Impact factor: 5.917
Authors: Gabriel Catano; Hemant Kulkarni; Weijing He; Vincent C Marconi; Brian K Agan; Michael Landrum; Stephanie Anderson; Judith Delmar; Vanessa Telles; Li Song; John Castiblanco; Robert A Clark; Matthew J Dolan; Sunil K Ahuja Journal: PLoS One Date: 2008-11-04 Impact factor: 3.240
Authors: Ping An; Sudhir Penugonda; Christian W Thorball; Istvan Bartha; James J Goedert; Sharyne Donfield; Susan Buchbinder; Elizabeth Binns-Roemer; Gregory D Kirk; Wenyan Zhang; Jacques Fellay; Xiao-Fang Yu; Cheryl A Winkler Journal: PLoS Genet Date: 2016-03-04 Impact factor: 5.917