Genome-Wide Association Study of Nevirapine Hypersensitivity in a sub-Saharan African HIV-infected Population

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Carr, DF, Bourgeois, S, Chaponda, M, Takeshita, L ORCID: 0000-0003-4288-4388, Morris, A, Cornejo Castro, EM, Alfirevic, A ORCID: 0000-0002-2801-9817, Jones, AR ORCID: 0000-0001-6118-9327, Rigden, DJ ORCID: 0000-0002-7565-8937, Haldenby, S et al (show 14 more authors) , Khoo, S ORCID: 0000-0002-2769-0967, Lalloo, DG ORCID: 0000-0001-7680-2200, Heyderman, RS, Dandara, C, Kampira, E, van Oosterhout, JJ, Ssali, F, Munderi, P, Novelli, G, Borgiani, P, Nelson, MR, Holden, A, Deloukas, P and Pirmohamed, M ORCID: 0000-0002-7534-7266 (2017) Genome-Wide Association Study of Nevirapine Hypersensitivity in a sub-Saharan African HIV-infected Population. Journal of Antimicrobial Chemotherapy, 72 (4). pp. 1152-1162.

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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.

Item Type:	Article
Uncontrolled Keywords:	Humans, HIV Infections, Stevens-Johnson Syndrome, Drug Hypersensitivity, Nevirapine, HLA-C Antigens, Anti-HIV Agents, Case-Control Studies, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Africa South of the Sahara, Female, Male, Genome-Wide Association Study, Young Adult, Biomarkers, Black People
Depositing User:	Symplectic Admin
Date Deposited:	14 Feb 2017 12:08
Last Modified:	13 Feb 2023 20:51
DOI:	10.1093/jac/dkw545
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3005648

Available Versions of this Item

• Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population. (deposited 21 Nov 2016 09:19)
  • Genome-Wide Association Study of Nevirapine Hypersensitivity in a sub-Saharan African HIV-infected Population. (deposited 14 Feb 2017 12:08) [Currently Displayed]