title: X chromosomal variation is associated with slow progression to AIDS in HIV-1-infected women.
abstract: AIDS has changed from a mostly male-specific health problem to one that predominantly affects females. Although sex differences in HIV-1 susceptibility are beyond doubt, the extent to which sex affects the onset and progression of AIDS has remained elusive. Here, we provide evidence for an influence of X chromosomal variation on the course of retroviral infection, both in HIV-1-infected patients and in the rhesus macaque model of AIDS. A two-stage, microsatellite-based GWAS of SIV-infected monkeys revealed MHC class I markers and a hitherto-unknown X chromosomal locus as being associated with a nominal score measuring progression to AIDS (Fisher's exact p < 10(-6)). The X chromosomal association was subsequently confirmed in HIV-1-infected patients with published SNP genotype data. SNP rs5968255, located at human Xq21.1 in a conserved sequence element near the RPS6KA6 and CYLC1 genes, was identified as a significant genetic determinant of disease progression in females (ANOVA p = 8.8 x 10(-5)), but not in males (p = 0.19). Heterozygous female carriers of the C allele showed significantly slower CD4 cell decline and a lower viral load at set point than TT homozygous females and than males. Inspection of HapMap revealed that the CT genotype is significantly more frequent among Asians than among Europeans or Africans. Our results suggest that, in addition to the individual innate and adaptive immunity status, sex-linked genetic variation impacts upon the rate of progression to AIDS. Elucidating the mechanisms underlying this sex-specific effect will promote the development of antiretroviral therapies with high efficacy in both sexes.
authors.affiliation: Genome Analysis, Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany. rsidd@fli-leibniz.de
authors.forename: Roman A
authors.initials: RA
authors.lastname: Siddiqui
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sauermann
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Elfriede
authors.initials: E
authors.lastname: Fritzer
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Nina
authors.initials: N
authors.lastname: Dalibor
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Kaup
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology / Q000821:virology; D000483:Alleles; D041321:Chromosomes, Human, X; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
references.citation: Nature. 1974 Aug 23;250(5468):651-3
references.pmid: 4851947
references.citation: J Virol. 2002 Jan;76(1):292-302
references.pmid: 11739694
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
references.pmid: 15075390
references.citation: Front Biosci. 2008 May 01;13:4258-75
references.pmid: 18508509
references.citation: Virology. 2009 Mar 15;385(2):425-33
references.pmid: 19135695
references.citation: Nat Genet. 2007 Oct;39(10):1217-24
references.pmid: 17873874
references.citation: Arch Dermatol. 2006 Mar;142(3):365-70
references.pmid: 16549716
references.citation: Nat Med. 1995 Dec;1(12):1279-83
references.pmid: 7489409
references.citation: Nat Rev Immunol. 2008 Sep;8(9):737-44
references.pmid: 18728636
references.citation: J Virol. 2004 Jan;78(1):275-84
references.pmid: 14671109
references.citation: Nat Genet. 2004 Jun;36(6):565-74
references.pmid: 15167933
references.citation: Curr Opin Immunol. 2005 Oct;17(5):510-6
references.pmid: 16084708
references.citation: J Immunol. 2002 Sep 15;169(6):3438-46
references.pmid: 12218167
references.citation: Science. 2005 Jun 10;308(5728):1582-3
references.pmid: 15947174
references.citation: J Antimicrob Chemother. 2007 Oct;60(4):724-32
references.pmid: 17715125
references.citation: Retrovirology. 2005 Dec 20;2:79
references.pmid: 16368003
references.citation: J Immunol. 2008 Nov 1;181(9):6406-16
references.pmid: 18941231
references.citation: Science. 1996 Aug 16;273(5277):959-63
references.pmid: 8688081
references.citation: Cytogenet Genome Res. 2007;116(1-2):24-8
references.pmid: 17268174
references.citation: Genome Res. 2005 Aug;15(8):1034-50
references.pmid: 16024819
references.citation: Genes Immun. 2008 Jan;9(1):69-80
references.pmid: 18094710
references.citation: N Engl J Med. 2001 Mar 8;344(10):720-5
references.pmid: 11236775
references.citation: Cell Host Microbe. 2008 Nov 13;4(5):495-504
references.pmid: 18976975
references.citation: Genome Res. 2004 Apr;14(4):708-15
references.pmid: 15060014
references.citation: Am J Hum Genet. 2004 Jan;74(1):106-20
references.pmid: 14681826
references.citation: J Acquir Immune Defic Syndr. 2002 Sep 1;31(1):11-9
references.pmid: 12352145
references.citation: Nat Rev Genet. 2008 Dec;9(12):911-22
references.pmid: 19002143
references.citation: Genome Res. 2008 Apr;18(4):640-3
references.pmid: 18256235
references.citation: Am J Epidemiol. 2008 Sep 1;168(5):532-40
references.pmid: 18663213
references.citation: Clin Cancer Res. 2008 Jul 15;14(14):4427-36
references.pmid: 18628456
references.citation: Science. 2008 Feb 15;319(5865):921-6
references.pmid: 18187620
references.citation: PLoS One. 2008;3(11):e3636
references.pmid: 18982067
references.citation: J Infect Dis. 2000 Sep;182(3):716-24
references.pmid: 10950764
references.citation: J Virol. 2003 Aug;77(16):9029-40
references.pmid: 12885919
references.citation: Am J Hum Genet. 2005 May;76(5):887-93
references.pmid: 15789306
references.citation: Nature. 2007 Apr 12;446(7137):801-5
references.pmid: 17325668
references.citation: Science. 2007 Aug 17;317(5840):944-7
references.pmid: 17641165
references.citation: Pediatrics. 2006 Jul;118(1):146-55
references.pmid: 16818560
references.citation: J Exp Med. 1997 Feb 17;185(4):621-8
references.pmid: 9034141
references.citation: Curr Biol. 2008 Aug 26;18(16):1241-8
references.pmid: 18691889
references.citation: J Virol. 2007 Oct;81(20):10914-23
references.pmid: 17670825
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Bioinformatics. 2006 Aug 1;22(15):1917-8
references.pmid: 16766553
references.citation: AIDS. 2005 Mar 24;19(6):577-83
references.pmid: 15802976
references.citation: AIDS Read. 2003 May;13(5):228-34, 239-40
references.pmid: 12800826
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: J Biol Chem. 2005 Apr 8;280(14):13304-14
references.pmid: 15632195
references.citation: PLoS One. 2009 Jun 17;4(6):e5950
references.pmid: 19536329
references.citation: Genomics. 2006 Jan;87(1):30-8
references.pmid: 16321502
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Gend Med. 2007 Dec;4(4):294-307
references.pmid: 18215722
references.citation: Cell. 2008 Oct 3;135(1):49-60
references.pmid: 18854154
references.citation: AIDS. 2007 Apr 23;21(7):835-43
references.pmid: 17415038
references.citation: Evolution. 1984 Nov;38(6):1358-1370
references.pmid: 28563791
references.citation: PLoS Med. 2008 Aug 12;5(8):e173
references.pmid: 18700814
references.citation: AIDS. 1999 Jan 14;13(1):31-9
references.pmid: 10207542
references.citation: Nat Med. 2008 Jun;14(6):617-21
references.pmid: 18535579
references.citation: Nature. 2005 Mar 17;434(7031):400-4
references.pmid: 15772666
references.citation: J Infect Dis. 2009 Feb 1;199(3):419-26
references.pmid: 19115949
references.citation: AIDS. 2009 Jan 2;23(1):19-28
references.pmid: 19050382
references.citation: Mol Immunol. 2005 Feb;42(2):251-8
references.pmid: 15488612