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

doi:10.1086/649842

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

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

61 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 language	English (US)
Pages (from-to)	618-626
Number of pages	9
Journal	Journal of Infectious Diseases
Volume	201
Issue number	4
DOIs	https://doi.org/10.1086/649842
State	Published - Feb 15 2010

Funding

Financial support: National Institutes of Health (NIH; R37 AI47734 to J.I.M. and T32 AI07140 to J.T.H.) and University of Washington Center for AIDS Research Genomics Core (P30 AI27757 to J.T.H. and J.I.M.). The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (NCI) and the National Heart, Lung and Blood Institute (UO1 AI35042, 5MO1 RR00722 [GCRC], UO1 AI35043, UO1 AI37984, UO1 AI35039, UO1 AI35040, UO1 AI37613, and UO1 AI35041); partial support was provided by the Intramural Research Program, NCI, NIH. The AIDS Link to the Intravenous Experience study was supported by the National Institute on Drug Abuse (R01-DA04334 and R01–12586). The San Francisco City Clinic Cohort Study was supported by the Centers for Disease Control and Prevention (U64/CCU900523–08).

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1086/649842

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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. (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

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

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.",

author = "Herbeck, {Joshua T.} and Gottlieb, {Geoffrey S.} and Winkler, {Cheryl A.} and Nelson, {George W.} and Ping An and Maust, {Brandon S.} and Wong, {Kim G.} and Troyer, {Jennifer L.} and Goedert, {James J.} and Kessing, {Bailey D.} and Roger Detels and Wolinsky, {Steven M.} and Jeremy Martinson and Susan Buchbinder and Kirk, {Gregory D.} and Jacobson, {Lisa P.} and Margolick, {Joseph B.} and Kaslow, {Richard A.} and O'Brien, {Stephen J.} and Mullins, {James I.}",

note = "Funding Information: Financial support: National Institutes of Health (NIH; R37 AI47734 to J.I.M. and T32 AI07140 to J.T.H.) and University of Washington Center for AIDS Research Genomics Core (P30 AI27757 to J.T.H. and J.I.M.). The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (NCI) and the National Heart, Lung and Blood Institute (UO1 AI35042, 5MO1 RR00722 [GCRC], UO1 AI35043, UO1 AI37984, UO1 AI35039, UO1 AI35040, UO1 AI37613, and UO1 AI35041); partial support was provided by the Intramural Research Program, NCI, NIH. The AIDS Link to the Intravenous Experience study was supported by the National Institute on Drug Abuse (R01-DA04334 and R01–12586). The San Francisco City Clinic Cohort Study was supported by the Centers for Disease Control and Prevention (U64/CCU900523–08).",

year = "2010",

month = feb,

day = "15",

doi = "10.1086/649842",

language = "English (US)",

volume = "201",

pages = "618--626",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "4",

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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

TY - JOUR

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 P.

AU - Margolick, Joseph B.

AU - Kaslow, Richard A.

AU - O'Brien, Stephen J.

AU - Mullins, James I.

N1 - Funding Information: Financial support: National Institutes of Health (NIH; R37 AI47734 to J.I.M. and T32 AI07140 to J.T.H.) and University of Washington Center for AIDS Research Genomics Core (P30 AI27757 to J.T.H. and J.I.M.). The Multicenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (NCI) and the National Heart, Lung and Blood Institute (UO1 AI35042, 5MO1 RR00722 [GCRC], UO1 AI35043, UO1 AI37984, UO1 AI35039, UO1 AI35040, UO1 AI37613, and UO1 AI35041); partial support was provided by the Intramural Research Program, NCI, NIH. The AIDS Link to the Intravenous Experience study was supported by the National Institute on Drug Abuse (R01-DA04334 and R01–12586). The San Francisco City Clinic Cohort Study was supported by the Centers for Disease Control and Prevention (U64/CCU900523–08).

PY - 2010/2/15

Y1 - 2010/2/15

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.

AB - 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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SN - 0022-1899

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JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 4

ER -

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

Abstract

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UN SDGs

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