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 Paula Jacobson, Joseph Bernard Margolick, Richard A. Kaslow, Stephen J. O'Brien, James I. Mullins

Research output: Contribution to journalArticle

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

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Virus Diseases
Disease Progression
HIV-1
Acquired Immunodeficiency Syndrome
Vascular Neoplasms
Kaposi's Sarcoma
Chromosomes, Human, Pair 1
Haplotypes
Interferons
Cohort Studies
Genotype
T-Lymphocytes
Population

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

Herbeck, J. T., Gottlieb, G. S., Winkler, C. A., Nelson, G. W., An, P., Maust, B. S., ... Mullins, J. I. (2010). Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS. Journal of Infectious Diseases, 201(4), 618-626. https://doi.org/10.1086/649842

Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS. / Herbeck, Joshua T.; Gottlieb, Geoffrey S.; Winkler, Cheryl A.; Nelson, George W.; An, Ping; Maust, Brandon S.; Wong, Kim G.; Troyer, Jennifer L.; Goedert, James J.; Kessing, Bailey D.; Detels, Roger; Wolinsky, Steven M.; Martinson, Jeremy; Buchbinder, Susan; Kirk, Gregory D; Jacobson, Lisa Paula; Margolick, Joseph Bernard; Kaslow, Richard A.; O'Brien, Stephen J.; Mullins, James I.

In: Journal of Infectious Diseases, Vol. 201, No. 4, 15.02.2010, p. 618-626.

Research output: Contribution to journalArticle

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 2010, 'Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS', Journal of Infectious Diseases, vol. 201, no. 4, pp. 618-626. https://doi.org/10.1086/649842
Herbeck, Joshua T. ; Gottlieb, Geoffrey S. ; Winkler, Cheryl A. ; Nelson, George W. ; An, Ping ; Maust, Brandon S. ; Wong, Kim G. ; Troyer, Jennifer L. ; Goedert, James J. ; Kessing, Bailey D. ; Detels, Roger ; Wolinsky, Steven M. ; Martinson, Jeremy ; Buchbinder, Susan ; Kirk, Gregory D ; Jacobson, Lisa Paula ; Margolick, Joseph Bernard ; Kaslow, Richard A. ; O'Brien, Stephen J. ; Mullins, James I. / Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS. In: Journal of Infectious Diseases. 2010 ; Vol. 201, No. 4. pp. 618-626.
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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.",
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T1 - Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS

AU - Herbeck, Joshua T.

AU - Gottlieb, Geoffrey S.

AU - Winkler, Cheryl A.

AU - Nelson, George W.

AU - An, Ping

AU - Maust, Brandon S.

AU - Wong, Kim G.

AU - Troyer, Jennifer L.

AU - Goedert, James J.

AU - Kessing, Bailey D.

AU - Detels, Roger

AU - Wolinsky, Steven M.

AU - Martinson, Jeremy

AU - Buchbinder, Susan

AU - Kirk, Gregory D

AU - Jacobson, Lisa Paula

AU - Margolick, Joseph Bernard

AU - Kaslow, Richard A.

AU - O'Brien, Stephen J.

AU - Mullins, James I.

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N2 - 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.

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