Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls.
Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10⁻¹¹). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Paul J
PJ
McLaren
Cédric
C
Coulonges
Stephan
S
Ripke
Leonard
L
van den Berg
Susan
S
Buchbinder
Mary
M
Carrington
Andrea
A
Cossarizza
Judith
J
Dalmau
Steven G
SG
Deeks
Olivier
O
Delaneau
Andrea
A
De Luca
James J
JJ
Goedert
David
D
Haas
Joshua T
JT
Herbeck
Sekar
S
Kathiresan
Gregory D
GD
Kirk
Olivier
O
Lambotte
Ma
M
Luo
Simon
S
Mallal
Daniëlle
D
van Manen
Javier
J
Martinez-Picado
Laurence
L
Meyer
José M
JM
Miro
James I
JI
Mullins
Niels
N
Obel
Stephen J
SJ
O'Brien
Florencia
F
Pereyra
Francis A
FA
Plummer
Guido
G
Poli
Ying
Y
Qi
Pierre
P
Rucart
Manj S
MS
Sandhu
Patrick R
PR
Shea
Hanneke
H
Schuitemaker
Ioannis
I
Theodorou
Fredrik
F
Vannberg
Jan
J
Veldink
Bruce D
BD
Walker
Amy
A
Weintrob
Cheryl A
CA
Winkler
Steven
S
Wolinsky
Amalio
A
Telenti
David B
DB
Goldstein
Paul I W
PI
de Bakker
Jean-François
JF
Zagury
Jacques
J
Fellay
D016022:Case-Control Studies; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000235:genetics* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D044465:White People