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.
Lane, J; McLaren, PJ; Dorrell, L; Shianna, KV; Stemke, A; Pelak, K; Moore, S; Oldenburg, J; Alvarez-Roman, MT; Angelillo-Scherrer, A; Boehlen, F; Bolton-Maggs, PHB; Brand, B; Brown, D; Chiang, E; Cid-Haro, AR; Clotet, B; Collins, P; 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, DA; 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, TT; Wolinsky, SM; Martinson, J; Hussain, SK; Bream, JH; Jacobson, LP; Carrington, M; Goedert, JJ; Haynes, BF; McMichael, AJ; Goldstein, DB; Fellay, J; NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI),
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