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

Jérôme Lane, Paul J. Mclaren, Lucy Dorrell, Kevin V. Shianna, Amanda Stemke, Kimberly Pelak, Stephen Moore, Johannes Oldenburg, Maria Teresa Alvarez-Roman, Anne Angelillo-Scherrer, Francoise Boehlen, Paula H B Bolton-Maggs, Brigit Brand, Deborah Brown, Elaine Chiang, Ana Rosa Cid-Haro, Bonaventura Clotet, Peter Collins, Sara Colombo, Judith DalmauPatrick Fogarty, Paul Giangrande, Alessandro Gringeri, Rathi Iyer, Olga Katsarou, Christine Kempton, Philip Kuriakose, Judith Lin, Mike Makris, Marilyn Manco-Johnson, Dimitrios A. Tsakiris, Javier Martinez-Picado, Evelien Mauser-Bunschoten, Anne Neff, Shinichi Oka, Lara Oyesiku, Rafael Parra, Kristiina Peter-Salonen, Jerry Powell, Michael Recht, Amy Shapiro, Kimo Stine, Katherine Talks, Amalio Telenti, Jonathan Wilde, Thynn Thynn Yee, Steven M. Wolinsky, Jeremy Martinson, Shehnaz K. Hussain, Jay H. Bream, Lisa P. Jacobson, Mary Carrington, James J. Goedert, Barton F. Haynes, Andrew J. Mcmichael, David B. Goldstein, Jacques Fellay

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberddt033
Pages (from-to)1903-1910
Number of pages8
JournalHuman Molecular Genetics
Volume22
Issue number9
DOIs
StatePublished - May 2013

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Genome-Wide Association Study
Hemophilia A
HIV Infections
Single Nucleotide Polymorphism
HIV-1
R Factors
Factor VIII
HIV
Genome
Virus Inactivation
Medical Genetics
Quality Control
Logistic Models
Phenotype
Mutation
Population

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Lane, J., Mclaren, P. J., Dorrell, L., Shianna, K. V., Stemke, A., Pelak, K., ... 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), 1903-1910. [ddt033]. https://doi.org/10.1093/hmg/ddt033

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, Vol. 22, No. 9, ddt033, 05.2013, p. 1903-1910.

Research output: Contribution to journalArticle

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 2013, 'A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A', Human Molecular Genetics, vol. 22, no. 9, ddt033, pp. 1903-1910. https://doi.org/10.1093/hmg/ddt033
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. / 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, No. 9. pp. 1903-1910.
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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.",
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AU - Pelak, Kimberly

AU - Moore, Stephen

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AU - Katsarou, Olga

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