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

Autores de IIS La Fe

• Jaime Dalmau Serra

  Autor

Participantes ajenos a IIS La Fe

• 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 PH
• Brand B
• Brown D
• Chiang E
• Cid-Haro AR
• Clotet B
• Collins P
• Colombo S
• 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)

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 32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 32 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.