| Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS. | |
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MedLine Citation:
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PMID: 20064070 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study. METHODS: The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters. RESULTS: Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fisher's combined P = 6.23 X 10(-7)). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P = 1.63 X 10(-6)). CONCLUSIONS: This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-gamma expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis. |
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Authors:
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Joshua T Herbeck; Geoffrey S Gottlieb; Cheryl A Winkler; George W Nelson; Ping An; Brandon S Maust; Kim G Wong; Jennifer L Troyer; James J Goedert; Bailey D Kessing; Roger Detels; Steven M Wolinsky; Jeremy Martinson; Susan Buchbinder; Gregory D Kirk; Lisa P Jacobson; Joseph B Margolick; Richard A Kaslow; Stephen J O'Brien; James I Mullins |
Publication Detail:
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Type: Journal Article; Multicenter Study; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of infectious diseases Volume: 201 ISSN: 1537-6613 ISO Abbreviation: J. Infect. Dis. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-25 Completed Date: 2010-03-08 Revised Date: 2012-05-16 |
Medline Journal Info:
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Nlm Unique ID: 0413675 Medline TA: J Infect Dis Country: United States |
Other Details:
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Languages: eng Pagination: 618-26 Citation Subset: AIM; IM |
Affiliation:
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Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070, USA. herbeck@u.washington.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acquired Immunodeficiency Syndrome
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genetics*,
pathology Adult Chromosomes, Human, Pair 1* Cohort Studies Disease Progression Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study / methods* HIV Infections / genetics*, pathology HIV-1* Homeodomain Proteins / genetics* Humans Linkage Disequilibrium Logistic Models Male Polymorphism, Single Nucleotide Proportional Hazards Models Tumor Suppressor Proteins / genetics* Viral Load |
| Grant Support | |
ID/Acronym/Agency:
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5M01 RR00722/RR/NCRR NIH HHS; P30 AI027757/AI/NIAID NIH HHS; P30 AI027757-119010/AI/NIAID NIH HHS; P30 AI027757-169012/AI/NIAID NIH HHS; P30 AI027757-21/AI/NIAID NIH HHS; P30 AI027757-219021/AI/NIAID NIH HHS; P30 AI27757/AI/NIAID NIH HHS; R01 DA004334/DA/NIDA NIH HHS; R01-1258//PHS HHS; R01-DA04334/DA/NIDA NIH HHS; R37 AI047734-06A1/AI/NIAID NIH HHS; R37 AI047734-12/AI/NIAID NIH HHS; R37 AI47734/AI/NIAID NIH HHS; T32 AI07140/AI/NIAID NIH HHS; U01 AI035040-18/AI/NIAID NIH HHS; U01 AI035042-10/AI/NIAID NIH HHS; U01 AI037984-04/AI/NIAID NIH HHS; U01 AI35039/AI/NIAID NIH HHS; U01 AI35040/AI/NIAID NIH HHS; U01 AI35041/AI/NIAID NIH HHS; U01 AI35042/AI/NIAID NIH HHS; U01 AI35043/AI/NIAID NIH HHS; U01 AI37613/AI/NIAID NIH HHS; U01 AI37984/AI/NIAID NIH HHS; U64/CCU900523-08//PHS HHS |
| Chemical | |
Reg. No./Substance:
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0/Homeodomain Proteins; 0/Tumor Suppressor Proteins; 0/prospero-related homeobox 1 protein |
| Comments/Corrections | |
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