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 Dalmau; Patrick 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

doi:10.1093/hmg/ddt033

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,

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	1903-1910
Number of pages	8
Journal	Human Molecular Genetics
Volume	22
Issue number	9
DOIs	https://doi.org/10.1093/hmg/ddt033
Publication status	Published - 2013

Keywords

Adult
DNA Copy Number Variations
Disease Resistance
Epistasis, Genetic
Factor VIII
Female
Gene Deletion
Genetic Predisposition to Disease
Genome-Wide Association Study
HIV Infections
HIV Seropositivity
Hemophilia A
Heterozygote
Homozygote
Humans
Logistic Models
Male
Meta-Analysis as Topic
Middle Aged
Phenotype
Polymorphism, Single Nucleotide
Prospective Studies
Receptors, CCR5

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10.1093/hmg/ddt033

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Lane, J., McLaren, P. J., Dorrell, L., Shianna, K. V., Stemke, A., Pelak, K., Moore, S., Oldenburg, J., Alvarez-Roman, M. T., Angelillo-Scherrer, A., Boehlen, F., Bolton-Maggs, P. H. B., Brand, B., Brown, D., Chiang, E., Cid-Haro, A. R., Clotet, B., Collins, P., Colombo, S. (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. https://doi.org/10.1093/hmg/ddt033

@article{01a25aed0fca40d99b70ce49a3c4cc5c,

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

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.",

keywords = "Adult, DNA Copy Number Variations, Disease Resistance, Epistasis, Genetic, Factor VIII, Female, Gene Deletion, Genetic Predisposition to Disease, Genome-Wide Association Study, HIV Infections, HIV Seropositivity, Hemophilia A, Heterozygote, Homozygote, Humans, Logistic Models, Male, Meta-Analysis as Topic, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Receptors, CCR5",

author = "J{\'e}r{\^o}me Lane and McLaren, {Paul J} and Lucy Dorrell and Shianna, {Kevin V} and Amanda Stemke and Kimberly Pelak and Stephen Moore and Johannes Oldenburg and Alvarez-Roman, {Maria Teresa} and Anne Angelillo-Scherrer and Francoise Boehlen and Bolton-Maggs, {Paula H B} and Brigit Brand and Deborah Brown and Elaine Chiang and Cid-Haro, {Ana Rosa} and Bonaventura Clotet and Peter Collins and Sara Colombo and Judith Dalmau and Patrick Fogarty and Paul Giangrande and Alessandro Gringeri and Rathi Iyer and Olga Katsarou and Christine Kempton and Philip Kuriakose and Judith Lin and Mike Makris and Marilyn Manco-Johnson and Tsakiris, {Dimitrios A} and Javier Martinez-Picado and Evelien Mauser-Bunschoten and Anne Neff and Shinichi Oka and Lara Oyesiku and Rafael Parra and Kristiina Peter-Salonen and Jerry Powell and Michael Recht and Amy Shapiro and Kimo Stine and Katherine Talks and Amalio Telenti and Jonathan Wilde and Yee, {Thynn Thynn} and Wolinsky, {Steven M} and Jeremy Martinson and Hussain, {Shehnaz K} and Bream, {Jay H}",

year = "2013",

doi = "10.1093/hmg/ddt033",

language = "English",

volume = "22",

pages = "1903--1910",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

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 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, pp. 1903-1910. https://doi.org/10.1093/hmg/ddt033

TY - JOUR

T1 - A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

AU - Lane, Jérôme

AU - McLaren, Paul J

AU - Dorrell, Lucy

AU - Shianna, Kevin V

AU - Stemke, Amanda

AU - Pelak, Kimberly

AU - Moore, Stephen

AU - Oldenburg, Johannes

AU - Alvarez-Roman, Maria Teresa

AU - Angelillo-Scherrer, Anne

AU - Boehlen, Francoise

AU - Bolton-Maggs, Paula H B

AU - Brand, Brigit

AU - Brown, Deborah

AU - Chiang, Elaine

AU - Cid-Haro, Ana Rosa

AU - Clotet, Bonaventura

AU - Collins, Peter

AU - Colombo, Sara

AU - Dalmau, Judith

AU - Fogarty, Patrick

AU - Giangrande, Paul

AU - Gringeri, Alessandro

AU - Iyer, Rathi

AU - Katsarou, Olga

AU - Kempton, Christine

AU - Kuriakose, Philip

AU - Lin, Judith

AU - Makris, Mike

AU - Manco-Johnson, Marilyn

AU - Tsakiris, Dimitrios A

AU - Martinez-Picado, Javier

AU - Mauser-Bunschoten, Evelien

AU - Neff, Anne

AU - Oka, Shinichi

AU - Oyesiku, Lara

AU - Parra, Rafael

AU - Peter-Salonen, Kristiina

AU - Powell, Jerry

AU - Recht, Michael

AU - Shapiro, Amy

AU - Stine, Kimo

AU - Talks, Katherine

AU - Telenti, Amalio

AU - Wilde, Jonathan

AU - Yee, Thynn Thynn

AU - Wolinsky, Steven M

AU - Martinson, Jeremy

AU - Hussain, Shehnaz K

AU - Bream, Jay H

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Adult

KW - DNA Copy Number Variations

KW - Disease Resistance

KW - Epistasis, Genetic

KW - Factor VIII

KW - Female

KW - Gene Deletion

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - HIV Infections

KW - HIV Seropositivity

KW - Hemophilia A

KW - Heterozygote

KW - Homozygote

KW - Humans

KW - Logistic Models

KW - Male

KW - Meta-Analysis as Topic

KW - Middle Aged

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Receptors, CCR5

U2 - 10.1093/hmg/ddt033

DO - 10.1093/hmg/ddt033

M3 - Article

C2 - 23372042

SN - 0964-6906

VL - 22

SP - 1903

EP - 1910

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 9

ER -

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

Abstract

Keywords

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