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 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.
authors.affiliation: Department of Microbiology, University of Washington School of Medicine, Seattle, WA 98195-8070, USA. herbeck@u.washington.edu
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Herbeck
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Gottlieb
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: George W
authors.initials: GW
authors.lastname: Nelson
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Maust
authors.forename: Kim G
authors.initials: KG
authors.lastname: Wong
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Troyer
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.forename: Bailey D
authors.initials: BD
authors.lastname: Kessing
authors.forename: Roger
authors.initials: R
authors.lastname: Detels
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolinsky
authors.forename: Jeremy
authors.initials: J
authors.lastname: Martinson
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Jacobson
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Margolick
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kaslow
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000473:pathology; D000328:Adult; D002878:Chromosomes, Human, Pair 1; D015331:Cohort Studies; D018450:Disease Progression; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D015658:HIV Infections / Q000235:genetics* / Q000473:pathology; D015497:HIV-1; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D019562:Viral Load; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein