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

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2010 Jan 13

PMID 20064070

Citations 42

Authors

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 OBrien

James I Mullins

Affiliations

Soon will be listed here.

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-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.

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References

OBrien S, Nelson G . Human genes that limit AIDS. Nat Genet. 2004; 36(6):565-74. DOI: 10.1038/ng1369. View

Huang B, Lin D . Efficient association mapping of quantitative trait loci with selective genotyping. Am J Hum Genet. 2007; 80(3):567-76. PMC: 1821103. DOI: 10.1086/512727. View

. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992; 41(RR-17):1-19. View

Carrington M, OBrien S . The influence of HLA genotype on AIDS. Annu Rev Med. 2003; 54:535-51. DOI: 10.1146/annurev.med.54.101601.152346. View

Migueles S, Sabbaghian M, Shupert W, Bettinotti M, Marincola F, Martino L . HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci U S A. 2000; 97(6):2709-14. PMC: 15994. DOI: 10.1073/pnas.050567397. View

Wang L, Zhu J, Shan S, Qin Y, Kong Y, Liu J . Repression of interferon-gamma expression in T cells by Prospero-related homeobox protein. Cell Res. 2009; 18(9):911-20. DOI: 10.1038/cr.2008.275. View

Herbeck J, Gottlieb G, Wong K, Detels R, Phair J, Rinaldo C . Fidelity of SNP array genotyping using Epstein Barr virus-transformed B-lymphocyte cell lines: implications for genome-wide association studies. PLoS One. 2009; 4(9):e6915. PMC: 2731852. DOI: 10.1371/journal.pone.0006915. View

Hendel H, Caillat-Zucman S, Lebuanec H, Carrington M, OBrien S, Andrieu J . New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS. J Immunol. 1999; 162(11):6942-6. View

Mellors J, Margolick J, Phair J, Rinaldo C, Detels R, Jacobson L . Prognostic value of HIV-1 RNA, CD4 cell count, and CD4 Cell count slope for progression to AIDS and death in untreated HIV-1 infection. JAMA. 2007; 297(21):2349-50. DOI: 10.1001/jama.297.21.2349. View

10.

Munoz A, Sabin C, Phillips A . The incubation period of AIDS. AIDS. 1997; 11 Suppl A:S69-76. View

11.

Chanock S, Manolio T, Boehnke M, Boerwinkle E, Hunter D, Thomas G . Replicating genotype-phenotype associations. Nature. 2007; 447(7145):655-60. DOI: 10.1038/447655a. View

12.

Limou S, Le Clerc S, Coulonges C, Carpentier W, Dina C, Delaneau O . Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). J Infect Dis. 2009; 199(3):419-26. DOI: 10.1086/596067. View

13.

Buchbinder S, Katz M, Hessol N, OMalley P, Holmberg S . Long-term HIV-1 infection without immunologic progression. AIDS. 1994; 8(8):1123-8. DOI: 10.1097/00002030-199408000-00014. View

14.

van Gestel S, Houwing-Duistermaat J, Adolfsson R, van Duijn C, Van Broeckhoven C . Power of selective genotyping in genetic association analyses of quantitative traits. Behav Genet. 2000; 30(2):141-6. DOI: 10.1023/a:1001907321955. View

15.

Vlahov D, Graham N, Hoover D, Flynn C, Bartlett J, Margolick J . Prognostic indicators for AIDS and infectious disease death in HIV-infected injection drug users: plasma viral load and CD4+ cell count. JAMA. 1998; 279(1):35-40. DOI: 10.1001/jama.279.1.35. View

16.

Ioannidis J, Rosenberg P, Goedert J, Ashton L, Benfield T, Buchbinder S . Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data. Ann Intern Med. 2001; 135(9):782-95. DOI: 10.7326/0003-4819-135-9-200111060-00008. View

17.

Dadras S, Skrzypek A, Nguyen L, Shin J, Schulz M, Arbiser J . Prox-1 promotes invasion of kaposiform hemangioendotheliomas. J Invest Dermatol. 2008; 128(12):2798-806. DOI: 10.1038/jid.2008.176. View

18.

Rappaport J, Cho Y, Hendel H, Schwartz E, Schachter F, Zagury J . 32 bp CCR-5 gene deletion and resistance to fast progression in HIV-1 infected heterozygotes. Lancet. 1997; 349(9056):922-3. DOI: 10.1016/S0140-6736(05)62697-9. View

19.

Ge D, Zhang K, Need A, Martin O, Fellay J, Urban T . WGAViewer: software for genomic annotation of whole genome association studies. Genome Res. 2008; 18(4):640-3. PMC: 2279251. DOI: 10.1101/gr.071571.107. View

20.

Dean M, Carrington M, Winkler C, Huttley G, Smith M, Allikmets R . Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort,.... Science. 1996; 273(5283):1856-62. DOI: 10.1126/science.273.5283.1856. View