Dataset Information

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

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*04:01 . In silico docking studies were also performed for HLA-C*04:01 .

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*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)].

Conclusions

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.

SUBMITTER: Carr DF

PROVIDER: S-EPMC5400091 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Publications

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

Carr Daniel F DF Bourgeois Stephane S Chaponda Mas M Takeshita Louise Y LY Morris Andrew P AP Castro Elena M Cornejo EM Alfirevic Ana A Jones Andrew R AR Rigden Daniel J DJ Haldenby Sam S Khoo Saye S Lalloo David G DG Heyderman Robert S RS Dandara Collet C Kampira Elizabeth E van Oosterhout Joep J JJ Ssali Francis F Munderi Paula P Novelli Giuseppe G Borgiani Paola P Nelson Matthew R MR Holden Arthur A Deloukas Panos P Pirmohamed Munir M

The Journal of antimicrobial chemotherapy 20170401 4

<h4>Background</h4>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).<h4>Objectives</h4>To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity.<h4>Methods</h4>A GWAS was undertaken in a discovery cohort of 151 ne ...[more]

PMID: 28062682

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Dataset Information

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

Background

Objectives

Methods

Results

Conclusions

Publications

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.

Similar Datasets

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