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Title

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Authors
Lane, Jérôme
McLaren, Paul J
Dorrell, Lucy
Shianna, Kevin V
Stemke, Amanda
Pelak, Kimberly
Moore, Stephen
Oldenburg, Johannes
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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 AdultDNA Copy Number VariationsDisease Resistance/geneticsEpistasis, GeneticFactor VIII/therapeutic useFemaleGene DeletionGenetic Predisposition to DiseaseGenome-Wide Association StudyHIV Infections/geneticsHIV Seropositivity/geneticsHemophilia A/geneticsHeterozygoteHomozygoteHumansLogistic ModelsMaleMeta-Analysis as TopicMiddle AgedPhenotypePolymorphism, Single NucleotideProspective StudiesReceptors, CCR5/genetics/metabolism
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PMID: 23372042
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LANE, Jérôme et al. 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

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Deposited on : 2016-12-02

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