Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.
J Antimicrob Chemother
; 72(4): 1152-1162, 2017 04 01.
Article
em En
| MEDLINE
| ID: mdl-28062682
ABSTRACT
Background:
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).Objectives:
To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity.Methods:
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*0401 . In silico docking studies were also performed for HLA-C*0401 .Results:
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*0401 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*0401 and ERAP1 , but there is a potential protective effect with ERAP2 [ P = 0.019, OR 0.43 (95% CI 0.21-0.87)].Conclusions:
HLA-C*0401 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.
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Base de dados:
MEDLINE
Assunto principal:
Antígenos HLA-C
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Infecções por HIV
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Fármacos Anti-HIV
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Nevirapina
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Polimorfismo de Nucleotídeo Único
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Hipersensibilidade a Drogas
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article