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Carr, Daniel F, Bourgeois, Stephane, Chaponda, Mas, Takeshita, Louise Y, Morris, Andrew P, Cornejo Castro, Elena M, Alfirevic, Ana, Jones, Andrew R, Rigden, Daniel J, Haldenby, Sam, Khoo, Saye, Lalloo, David 
ORCID: https://orcid.org/0000-0001-7680-2200, Heyderman, Robert, Dandara, Collet, Kampira, Elizabeth, van Oosterhout, Joep J, Ssali, Francis, Munderi, Paula, Novelli, Giuseppe, Borgiani, Paola, Nelson, Matthew R, Holden, Arthur, Deloukas, Panos and Pirmohamed, Munir
(2017)
'Genome-Wide Association Study of Nevirapine Hypersensitivity in a sub-Saharan African HIV-infected Population'. Journal of Antimicrobial Chemotherapy, Vol 72, Issue 4, pp. 1152-1162.
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NVP_GWAS_SAEC_SB_pd_APM_MP_new_imputation_LT_MP_August_post-review.doc - Accepted Version Available under License Creative Commons Attribution. Download (1MB) |
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J_Antimic_Chemo_72_4_1152-1162_2017.pdf - Published Version Available under License Creative Commons Attribution. Download (666kB) | Preview |
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).
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.
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