title: Genome-wide association study implicates PARD3B-based AIDS restriction.
abstract: BACKGROUND
  Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression.
  
  
  METHODS
  European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model).
  
  
  RESULTS
  Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10(-9)) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10(-8)). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025).
  
  
  CONCLUSIONS
  These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression.
authors.affiliation: Laboratory of Genomic Diversity, SAIC-Frederick, Inc., Frederick, MD 21702, USA. troyerj@mail.nih.gov
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Troyer
authors.forename: George W
authors.initials: GW
authors.lastname: Nelson
authors.forename: James A
authors.initials: JA
authors.lastname: Lautenberger
authors.forename: Leslie
authors.initials: L
authors.lastname: Chinn
authors.forename: Carl
authors.initials: C
authors.lastname: McIntosh
authors.forename: Randall C
authors.initials: RC
authors.lastname: Johnson
authors.forename: Efe
authors.initials: E
authors.lastname: Sezgin
authors.forename: Bailey
authors.initials: B
authors.lastname: Kessing
authors.forename: Michael
authors.initials: M
authors.lastname: Malasky
authors.forename: Sher L
authors.initials: SL
authors.lastname: Hendrickson
authors.forename: Guan
authors.initials: G
authors.lastname: Li
authors.forename: Joan
authors.initials: J
authors.lastname: Pontius
authors.forename: Minzhong
authors.initials: M
authors.lastname: Tang
authors.forename: Ping
authors.initials: P
authors.lastname: An
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: Sophie
authors.initials: S
authors.lastname: Limou
authors.forename: Sigrid
authors.initials: S
authors.lastname: Le Clerc
authors.forename: Olivier
authors.initials: O
authors.lastname: Delaneau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Zagury
authors.forename: Hanneke
authors.initials: H
authors.lastname: Schuitemaker
authors.forename: Daniëlle
authors.initials: D
authors.lastname: van Manen
authors.forename: Jay H
authors.initials: JH
authors.lastname: Bream
authors.forename: Edward D
authors.initials: ED
authors.lastname: Gomperts
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002874:Chromosome Mapping; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000276:immunology*; D015894:Genome, Human; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C471157:PARD3B protein, human