A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A
Lane, Jérôme ; McLaren, Paul J. ; Dorrell, Lucy ; Shianna, Kevin V. ; Stemke, Amanda ; Pelak, Kimberly ; Moore, Stephen ; Oldenburg, Johannes ; Alvarez-Roman, Maria Teresa ; Angelillo-Scherrer, Anne ; Boehlen, Francoise ; Bolton-Maggs, Paula H.B. ; Brand, Brigit ; Brown, Deborah ; Chiang, Elaine ; Cid-Haro, Ana Rosa ; Clotet, Bonaventura ; Collins, Peter ; Colombo, Sara ; Dalmau, Judith ; Fogarty, Patrick ; Giangrande, Paul ; Gringeri, Alessandro ; Iyer, Rathi ; Katsarou, Olga ; Kempton, Christine ; Kuriakose, Philip ; Lin, Judith ; Makris, Mike ; Manco-Johnson, Marilyn ; Tsakiris, Dimitrios A. ; Martinez-Picado, Javier ; Mauser-Bunschoten, Evelien ; Neff, Anne ; Oka, Shinichi ; Oyesiku, Lara ; Parra, Rafael ; Peter-Salonen, Kristiina ; Powell, Jerry ; Recht, Michael ; Shapiro, Amy ; Stine, Kimo ; Talks, Katherine ; Telenti, Amalio ; Wilde, Jonathan ; Yee, Thynn Thynn ; Wolinsky, Steven M. ; Martinson, Jeremy ; Hussain, Shehnaz K. ; Bream, Jay H. ; Jacobson, Lisa P. ; Carrington, Mary ; Goedert, James J. ; Haynes, Barton F. ; McMichael, Andrew J. ; Goldstein, David B. ; Fellay, Jacques
In: Human Molecular Genetics, 2013, vol. 22, no. 9, p. 1903-1910
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- 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