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

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).

Objective: 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<1x10-5) 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<8.5x10-8) and was below HLA-wide significance (p<2.5x10-4) 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 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 allele. Whether this risk is modulated by ERAP2 variants requires further study.