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Multistage Genomewide Association Study Identifies a Locus at 1q41 Associated with Rate of HIV-1 Disease Progression to Clinical AIDS

  1. Author:
    Herbeck, J. T.
    Gottlieb, G. S.
    Winkler, C. A.
    Nelson, G. W.
    An, P.
    Maust, B. S.
    Wong, K. G.
    Troyer, J. L.
    Goedert, J. J.
    Kessing, B. D.
    Detels, R.
    Wolinsky, S. M.
    Martinson, J.
    Buchbinder, S.
    Kirk, G. D.
    Jacobson, L. P.
    Margolick, J. B.
    Kaslow, R. A.
    O'Brien, S. J.
    Mullins, J. I.

  2. Author Address

    [Herbeck, Joshua T.; Maust, Brandon S.; Wong, Kim G.; Mullins, James I.] Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA. [Gottlieb, Geoffrey S.; Mullins, James I.] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Winkler, Cheryl A.; Nelson, George W.; An, Ping; Troyer, Jennifer L.; Kessing, Bailey D.] SAIC Frederick, Lab Genom Divers Basic Res Program, Frederick, MD USA. [O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. [Kirk, Gregory D.; Jacobson, Lisa P.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Margolick, Joseph B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Detels, Roger] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Buchbinder, Susan] San Francisco Dept Publ Hlth, HIV Res Sect, San Francisco, CA USA. [Wolinsky, Steven M.] Northwestern Univ, Feinberg Sch Med, Div Infect Dis, Chicago, IL 60611 USA. [Martinson, Jeremy] Univ Pittsburgh, Dept Infect Dis & Microbiol, Pittsburgh, PA USA. [Kaslow, Richard A.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA.;Herbeck, JT, Univ Washington, Sch Med, Dept Microbiol, Seattle, WA 98195 USA.;herbeck@u.washington.edu
    1. Year: 2010
    2. Date: Feb
  2. Journal: Journal of Infectious Diseases
    1. 201
    2. 4
    3. Pages: 618-626
  4. Type of Article: Article
  5. ISSN: 0022-1899
  1. Abstract:

    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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External Sources

  1. View Full Text
  2. DOI: 10.1086/649842
  3. View record in Web of Science®
  4. WOS: 000273843900019

Library Notes

  1. Fiscal Year: FY2009-2010
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