Multiple-cohort genetic association study reveals CXCR6 as a new chemokine receptor involved in long-term nonprogression to AIDS.
BACKGROUND
The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS.


METHODS
To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding "elite controller" patients, who were controlling the viral load at very low levels (<100 copies/mL).


RESULTS
The rs2234358 polymorphism in the CXCR6 gene was the strongest signal (P=2.5 x 10(-7); odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of P(combined)=9.7 x 10(-10). This association with LTNP is independent of the CCR2-CCR5 locus and the HCP5 polymorphisms.


CONCLUSIONS
The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.
Limou
Sophie
S
Chaire de Bioinformatique, Conservatoire National des Arts et Métiers.
Coulonges
Cédric
C
Herbeck
Joshua T
JT
van Manen
Daniëlle
D
An
Ping
P
Le Clerc
Sigrid
S
Delaneau
Olivier
O
Diop
Gora
G
Taing
Lieng
L
Montes
Matthieu
M
van't Wout
Angélique B
AB
Gottlieb
Geoffrey S
GS
Therwath
Amu
A
Rouzioux
Christine
C
Delfraissy
Jean-François
JF
Lelièvre
Jean-Daniel
JD
Lévy
Yves
Y
Hercberg
Serge
S
Dina
Christian
C
Phair
John
J
Donfield
Sharyne
S
Goedert
James J
JJ
Buchbinder
Susan
S
Estaquier
Jérôme
J
Schächter
François
F
Gut
Ivo
I
Froguel
Philippe
P
Mullins
James I
JI
Schuitemaker
Hanneke
H
Winkler
Cheryl
C
Zagury
Jean-François
JF
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology*; D015331:Cohort Studies; D056726:Genetic Association Studies; D020276:HIV Long-Term Survivors; D015497:HIV-1; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D011110:Polymorphism, Genetic; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000235:genetics* / Q000276:immunology; D011991:Receptors, Virus / Q000235:genetics* / Q000276:immunology
C106330:CXCR6 protein, human; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus