Screening low-frequency SNPS from genome-wide association study reveals a new risk allele for progression to AIDS.
BACKGROUND
Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance.


METHODS
We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency <5%). Two groups composed of 365 slow progressors and 147 rapid progressors from Europe and the United States were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections.


RESULTS
Of the 8584 SNPs with minor allele frequency <5% in cases and controls (Bonferroni threshold = 5.8 × 10⁻⁶), 4 SNPs showed statistical evidence of association with the slow progressor phenotype. The best result was for HCP5 rs2395029 [P = 8.54 × 10⁻¹⁵, odds ratio (OR) = 3.41] in the HLA locus, in partial linkage disequilibrium with 2 additional chromosome 6 associations in C6orf48 (P = 3.03 × 10⁻¹⁰, OR = 2.9) and NOTCH4 (9.08 × 10⁻⁰⁷, OR = 2.32). The fourth association corresponded to rs2072255 located in RICH2 (P = 3.30 × 10⁻⁰⁶, OR = 0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant.


CONCLUSIONS
Besides the already known chromosome 6 associations, the analysis of low-frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low-frequency SNPs to exploit GWAS data.
Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France.
Sigrid
S
Le Clerc
Cédric
C
Coulonges
Olivier
O
Delaneau
Danielle
D
Van Manen
Joshua T
JT
Herbeck
Sophie
S
Limou
Ping
P
An
Jeremy J
JJ
Martinson
Jean-Louis
JL
Spadoni
Amu
A
Therwath
Jan H
JH
Veldink
Leonard H
LH
van den Berg
Lieng
L
Taing
Taoufik
T
Labib
Safa
S
Mellak
Matthieu
M
Montes
Jean-François
JF
Delfraissy
François
F
Schächter
Cheryl
C
Winkler
Philippe
P
Froguel
James I
JI
Mullins
Hanneke
H
Schuitemaker
Jean-François
JF
Zagury
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D000328:Adult; D000483:Alleles; D018450:Disease Progression; D005060:Europe; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020276:HIV Long-Term Survivors; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014481:United States
C539906:ARHGAP44 protein, human; D020690:GTPase-Activating Proteins