Multistage Genomewide Association Study Identifies... [J Infect Dis. 2009] - PubMed result

J Infect Dis. 2009 Dec 29. [Epub ahead of print]

Multistage Genomewide Association Study Identifies a Locus at 1q41 Associated with Rate of HIV-1 Disease Progression to Clinical AIDS.
Herbeck JT, Gottlieb GS, Winkler CA, Nelson GW, An P, Maust BS, Wong KG, Troyer JL, Goedert JJ, Kessing BD, Detels R, Wolinsky SM, Martinson J, Buchbinder S, Kirk GD, Jacobson LP, Margolick JB, Kaslow RA, O'Brien SJ, Mullins JI.

Departments of 1Microbiology and 2Medicine, University of Washington School of Medicine, Seattle; 3Laboratory of Genomic Diversity Basic Research Program, SAIC-Frederick, and 4Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Frederick, 5Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, and Departments of 6Epidemiology and 7Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; 8Department of Epidemiology, School of Public Health, University of California, Los Angeles, and 9San Francisco Department of Public Health, HIV Research Section, San Francisco; 10Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; 11Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania; 12Department of Epidemiology, University of Alabama at Birmingham, Birmingham.

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 [Formula: see text]). 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 [Formula: see text]). 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.

PMID: 20064070 [PubMed - as supplied by publisher]

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Multistage Genomewide Association Study Identifies... [J Infect Dis. 2009] - PubMed result