LSTM Home > LSTM Research > LSTM Online Archive

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

Downloads

Downloads per month over past year

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.

[img] Text
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)
[img] Text
Supplementary data_add.docx - Supplemental Material
Available under License Creative Commons Attribution.

Download (107kB)
[img]
Preview
Text
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.

Item Type: Article
Subjects: QU Biochemistry > Genetics > QU 460 Genomics. Proteomics
QZ Pathology > Pathogenesis. Etiology > QZ 40 Pathogenesis. Etiology
WA Public Health > Health Problems of Special Population Groups > WA 300 General. Refugees
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503 Acquired immunodeficiency syndrome. HIV infections
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.2 Therapy
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.5 Complications
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Clinical Sciences & International Health > International Public Health Department
Digital Object Identifer (DOI): https://doi.org/10.1093/jac/dkw545
Depositing User: Jessica Jones
Date Deposited: 08 Dec 2016 15:50
Last Modified: 20 Nov 2017 02:02
URI: https://archive.lstmed.ac.uk/id/eprint/6425

Statistics

View details

Actions (login required)

Edit Item Edit Item