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

Lane, J., McLaren, P., Dorrell, L., Shianna, K., Stemke, A., Pelak, K., Moore, S., Oldenburg, J., Alvarez-Roman, M., Angelillo-Scherrer, A., Boehlen, F., Bolton-Maggs, P., Brand, B., Brown, D., Chiang, E., Cid-Haro, A., Clotet, B., Collins, Peter William, Colombo, S., Dalmau, J., Fogarty, P., Giangrande, P., Gringeri, A., Iyer, R., Katsarou, O., Kempton, C., Kuriakose, P., Lin, J., Makris, M., Manco-Johnson, M., Tsakiris, D., Martinez-Picado, J., Mauser-Bunschoten, E., Neff, A., Oka, S., Oyesiku, L., Parra, R., Peter-Salonen, K., Powell, J., Recht, M., Shapiro, A., Stine, K., Talks, K., Telenti, A., Wilde, J., Yee, T., Wolinsky, S., Martinson, J., Hussain, S., Bream, J., Jacobson, L., Carrington, M., Goedert, J., Haynes, B., McMichael, A., Goldstein, D. and Fellay, J. 2013. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A. Human Molecular Genetics 22 (9) , pp. 1903-1910. 10.1093/hmg/ddt033

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: Adult; Disease Resistance; DNA Copy Number Variations; Epistasis, Genetic; Factor VIII; Female; Gene Deletion; Genetic Predisposition to Disease; Genome-Wide Association Study; Hemophilia A; Heterozygote; HIV Infections; HIV Seropositivity; Homozygote; Humans; Logistic Models; Male; Meta-Analysis as Topic; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Prospective Studies; Receptors, CCR5
Publisher: Oxford University Press
ISSN: 0964-6906
Date of Acceptance: 28 January 2013
Last Modified: 04 Jun 2017 08:21
URI: http://orca.cf.ac.uk/id/eprint/76270

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