Genomewide association study of a rapid progression cohort identifies new susceptibility alleles for AIDS (ANRS Genomewide Association Study 03).
BACKGROUND
Previous genomewide association studies (GWASs) of AIDS have targeted end points based on the control of viral load and disease nonprogression. The discovery of genetic factors that predispose individuals to rapid progression to AIDS should also reveal new insights into the molecular etiology of the pathology.


METHODS
We undertook a case-control GWAS of a unique cohort of 85 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced rapid disease progression, using Illumina HumanHap300 BeadChips. The case group was compared with a control group of 1352 individuals for the 291,119 autosomal single-nucleotide polymorphisms (SNPs) passing the quality control tests, using the false-discovery rate (FDR) statistical method for multitest correction.


RESULTS
Novel associations with rapid progression (FDR, < or = 25%) were identified for PRMT6 (P = 6.1 x 10(-7); odds ratio [OR], 0.24), SOX5 (P = 1.8 x 10(-6); OR, 0.45), RXRG (P = 3.9 x 10(-6); OR, 3.29), and TGFBRAP1 (P = 7 x 10(-6); OR, 0.34). The haplotype analysis identified exonic and promoter SNPs potentially important for PRMT6 and TGFBRAP1 function.


CONCLUSIONS
The statistical and biological relevance of these associations and their high ORs underscore the power of extreme phenotypes for GWASs, even with a modest sample size. These genetic results emphasize the role of the transforming growth factor beta pathway in the pathogenesis of HIV-1 disease. Finally, the wealth of information provided by this study should help unravel new diagnostic and therapeutic targets.
Le Clerc
Sigrid
S
Conservatoire National des Arts et Métiers, Paris, France.
Limou
Sophie
S
Coulonges
Cédric
C
Carpentier
Wassila
W
Dina
Christian
C
Taing
Lieng
L
Delaneau
Olivier
O
Labib
Taoufik
T
Sladek
Rob
R
Deveau
Christiane
C
Guillemain
Hélène
H
Ratsimandresy
Rojo
R
Montes
Matthieu
M
Spadoni
Jean-Louis
JL
Therwath
Amu
A
Schächter
François
F
Matsuda
Fumihiko
F
Gut
Ivo
I
Lelièvre
Jean-Daniel
JD
Lévy
Yves
Y
Froguel
Philippe
P
Delfraissy
Jean-François
JF
Hercberg
Serge
S
Zagury
Jean-François
JF
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006679:HIV Seropositivity; D006801:Humans; D015810:Linkage Disequilibrium; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide