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A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.
|Published in||Human Molecular Genetics. 2013, vol. 22, no. 9, p. 1903-1910|
|Abstract||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.|
|Keywords||Adult — DNA Copy Number Variations — Disease Resistance/genetics — Epistasis, Genetic — Factor VIII/therapeutic use — Female — Gene Deletion — Genetic Predisposition to Disease — Genome-Wide Association Study — HIV Infections/genetics — HIV Seropositivity/genetics — Hemophilia A/genetics — Heterozygote — Homozygote — Humans — Logistic Models — Male — Meta-Analysis as Topic — Middle Aged — Phenotype — Polymorphism, Single Nucleotide — Prospective Studies — Receptors, CCR5/genetics/metabolism|
|LANE, Jérôme, BOEHLEN, Françoise. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A. In: Human Molecular Genetics, 2013, vol. 22, n° 9, p. 1903-1910. https://archive-ouverte.unige.ch/unige:89770|