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.

Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles

“…This agrees with an independent analysis by Carr et al . 32 Not all identified HLA-C risk alleles carry Phe99, the exception being HLA-C*05: 01 which carries Tyr99 and other B pocket residues in common with non-risk alleles (Fig. 1E ).…”

An Overview on ERAP Roles in Infectious Diseases

“…In addition, interesting results showed that ERAP2 polymorphisms (rs2549782 and rs2248374) strongly associate with hypersensitivity syndrome to nevirapine in subjects carrying the HLA-C*04:01 allele. Notably, this report is the first one to investigate the interaction between drug-induced HLA disease and the ERAP gene [114].…”

Clinical and pathogenic aspects of the severe cutaneous adverse reaction epidermal necrolysis (EN)

“…Recently, a preferential TCR clonotype was identified, binding to carbamazepine which can subsequently constitute the interaction between this TCR and HLA‐B*15:2 114 . Regarding the sequence and quantity of the peptide presented by the HLA, variants in genes related to proteasomal function or peptide generation can contribute to the risk for EN 120,122,123 . The function of metabolic genes and drug transporters influence the availability of the drug (metabolite) involved in the TCR‐HLA interaction.…”