title: Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.
abstract: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).
  
  
  
  To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity.
  
  
  
  A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensitive and 182 tolerant, HIV-infected Malawian adults. Replication of signals was determined in a cohort of 116 cases and 68 controls obtained from Malawi, Uganda and Mozambique. Interaction with ERAP genes was determined in patients positive for HLA-C*04:01 . In silico docking studies were also performed for HLA-C*04:01 .
  
  
  
  Fifteen SNPs demonstrated nominal significance ( P  <   1 × 10 -5 ) with one or more of the hypersensitivity phenotypes. The most promising signal was seen in SJS/TEN, where rs5010528 ( HLA-C locus) approached genome-wide significance ( P  <   8.5 × 10 -8 ) and was below HLA -wide significance ( P  <   2.5 × 10 -4 ) in the meta-analysis of discovery and replication cohorts [OR 4.84 (95% CI 2.71-8.61)]. rs5010528 is a strong proxy for HLA-C*04:01 carriage: in silico docking showed that two residues (33 and 123) in the B pocket were the most likely nevirapine interactors. There was no interaction between HLA-C*04:01 and ERAP1 , but there is a potential protective effect with ERAP2 [ P  =   0.019, OR 0.43 (95% CI 0.21-0.87)].
  
  
  
  HLA-C*04:01 predisposes to nevirapine-induced SJS/TEN in sub-Saharan Africans, but not to other hypersensitivity phenotypes. This is likely to be mediated via binding to the B pocket of the HLA-C peptide. Whether this risk is modulated by ERAP2 variants requires further study.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Carr
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Stephane
authors.initials: S
authors.lastname: Bourgeois
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.|Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.
authors.forename: Mas
authors.initials: M
authors.lastname: Chaponda
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Louise Y
authors.initials: LY
authors.lastname: Takeshita
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.|Department of Biostatistics, University of Liverpool, Liverpool, UK.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Elena M Cornejo
authors.initials: EM
authors.lastname: Castro
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Alfirevic
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Jones
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rigden
authors.affiliation: Centre for Genomic Research, University of Liverpool, Liverpool, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Haldenby
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.|Division of Infection and Immunity, University College London, London, UK.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Heyderman
authors.affiliation: Division of Human Genetics, University of Cape Town, Cape Town, South Africa.
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
authors.affiliation: Division of Human Genetics, University of Cape Town, Cape Town, South Africa.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kampira
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.|Dignitas International, Zomba, Malawi.
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.affiliation: Joint Clinical Research Centre, Headquarters, Kampala, Uganda.
authors.forename: Francis
authors.initials: F
authors.lastname: Ssali
authors.affiliation: UVRI/MRC Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: Paula
authors.initials: P
authors.lastname: Munderi
authors.affiliation: Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.affiliation: Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Borgiani
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.affiliation: SAEC Consortium, Ltd, Chicago, IL, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Holden
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D044383:Black People; D016022:Case-Control Studies; D004342:Drug Hypersensitivity / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics / Q000821:virology; D015236:HLA-C Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D013262:Stevens-Johnson Syndrome / Q000209:etiology; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D015236:HLA-C Antigens; D019829:Nevirapine