Biology Faculty Articles

Title

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

Document Type

Article

Publication Date

2-15-2010

Publication Title

Journal of Infectious Diseases

ISSN

0022-1899

Volume

201

Issue/No.

4

First Page

618

Last Page

626

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-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.

Comments

©2010 by the Infectious Diseases Society of America. All rights reserved.

Additional Comments

National Institutes of Health contract #s: R37 AI47734, T32 AI07140; University of Washington Center for AIDS Research Genomics Core grant #: P30 AI27757; National Institute of Allergy and Infectious Diseases grant #s: UO1 AI35042, 5MO1 RR00722, UO1 AI35043, UO1 AI37984, UO1 AI35039, UO1 AI35040, UO1 AI37613, UO1 AI35041; National Institute on Drug Abuse grant #s: R01-DA04334, R01–12586; Centers for Disease Control and Prevention grant #: U64/CCU900523–08

ORCID ID

0000-0001-7353-8301

ResearcherID

N-1726-2015

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