Volume 4 Supplement 3
Genome-wide association study of nevirapine hypersensitivity in a malawian HIV-infected population
© Carr et al; licensee BioMed Central Ltd. 2014
Published: 18 July 2014
The non-nucleoside reverse transcriptase inhibitor nevirapine is used in the treatment of HIV in many developing countries. Its use is associated with occurrence of hypersensitivity in 6-10% of patients. This hypersensitivity can manifest as a number of phenotypes which include the severe skin blistering reactions Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The aim was to undertake a genome wide association study (GWAS) in order to identify genetic variants associated with predisposition to nevirapine-induced hypersensitivity. A total of 333 nevirapine-exposed (151 hypersensitive and 182 tolerant) , HIV-infected Malawian adults were genotyped for 826,551 genotyped SNPs using the Illumina HumanOmni1-Quad_v1 chip. A replication cohort of 62 hypersensitive and 59 tolerant patients from Malawi and Uganda was genotyped for 40 SNPs statistically significantly associated with a hypersensitive phenotype in the main cohort (p<5x10-5) using the Sequenom iPLEX platform or TaqMan allelic discrimination. Logistic regression analysis identified 40 statistically significant SNP signals associated with a nevirapine hypersensitivity phenotype. Only 1 SNP association signal (in the HLA-C locus, associated with SJS/TEN) was statistically significant in both our main discovery (=1.48x10-6) and enriched replication cohort (38 cases and 59 controls) (p=9.6x10-5). Meta-analysis determined the odds ratio as 5.17 (p=2.61x10-10). Data suggest this SNP to be a strong proxy for HLA-C*04:01 carriage (96% co-occurrence). We have confirmed that, in a sub-Saharan African population, HLA-C*04:01 carriage confers a significant risk for nevirapine-induced SJS_TEN though not to less severe hypersensitivity phenotypes. No other significant high penetrance genetic risk factors were identified.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.