A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Jérôme
J
Lane
Paul J
PJ
McLaren
Lucy
L
Dorrell
Kevin V
KV
Shianna
Amanda
A
Stemke
Kimberly
K
Pelak
Stephen
S
Moore
Johannes
J
Oldenburg
Maria Teresa
MT
Alvarez-Roman
Anne
A
Angelillo-Scherrer
Francoise
F
Boehlen
Paula H B
PH
Bolton-Maggs
Brigit
B
Brand
Deborah
D
Brown
Elaine
E
Chiang
Ana Rosa
AR
Cid-Haro
Bonaventura
B
Clotet
Peter
P
Collins
Sara
S
Colombo
Judith
J
Dalmau
Patrick
P
Fogarty
Paul
P
Giangrande
Alessandro
A
Gringeri
Rathi
R
Iyer
Olga
O
Katsarou
Christine
C
Kempton
Philip
P
Kuriakose
Judith
J
Lin
Mike
M
Makris
Marilyn
M
Manco-Johnson
Dimitrios A
DA
Tsakiris
Javier
J
Martinez-Picado
Evelien
E
Mauser-Bunschoten
Anne
A
Neff
Shinichi
S
Oka
Lara
L
Oyesiku
Rafael
R
Parra
Kristiina
K
Peter-Salonen
Jerry
J
Powell
Michael
M
Recht
Amy
A
Shapiro
Kimo
K
Stine
Katherine
K
Talks
Amalio
A
Telenti
Jonathan
J
Wilde
Thynn Thynn
TT
Yee
Steven M
SM
Wolinsky
Jeremy
J
Martinson
Shehnaz K
SK
Hussain
Jay H
JH
Bream
Lisa P
LP
Jacobson
Mary
M
Carrington
James J
JJ
Goedert
Barton F
BF
Haynes
Andrew J
AJ
McMichael
David B
DB
Goldstein
Jacques
J
Fellay
D000328:Adult; D056915:DNA Copy Number Variations; D060467:Disease Resistance / Q000235:genetics*; D004843:Epistasis, Genetic; D005169:Factor VIII / Q000627:therapeutic use; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015658:HIV Infections / Q000235:genetics*; D006679:HIV Seropositivity / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016015:Logistic Models; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism
D019713:Receptors, CCR5; D005169:Factor VIII