Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.
J Antimicrob Chemother
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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.
AuthorsCarr, DF; Bourgeois, S; Chaponda, M; Takeshita, LY; Morris, AP; Castro, EMC; Alfirevic, A; Jones, AR; Rigden, DJ; Haldenby, S; Khoo, S; Lalloo, DG; Heyderman, RS; Dandara, C; Kampira, E; van Oosterhout, JJ; Ssali, F; Munderi, P; Novelli, G; Borgiani, P; Nelson, MR; Holden, A; Deloukas, P; Pirmohamed, M
- Cardiovascular