Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS

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

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

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 × 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 × 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-γ 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.

Original languageEnglish (US)
Pages (from-to)618-626
Number of pages9
JournalJournal of Infectious Diseases
Volume201
Issue number4
DOIs
StatePublished - Feb 15 2010

ASJC Scopus subject areas

  • General Medicine

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