Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.
Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population.
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DOI：
10.1093/jac/dkw545
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发表时间：
2017-04-01
期刊：
影响因子：
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通讯作者：
Pirmohamed M
中科院分区：
文献类型：
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作者：
Carr DF;Bourgeois S;Chaponda M;Takeshita LY;Morris AP;Castro EM;Alfirevic A;Jones AR;Rigden DJ;Haldenby S;Khoo S;Lalloo DG;Heyderman RS;Dandara C;Kampira E;van Oosterhout JJ;Ssali F;Munderi P;Novelli G;Borgiani P;Nelson MR;Holden A;Deloukas P;Pirmohamed M
背景资料：抗逆转录病毒奈韦拉平与6%-10%患者的超敏反应相关，包括肝毒性、斑丘疹性外显、Stevens-Johnson综合征（SJS）和中毒性表皮坏死松解症（TEN）。目的：进行全基因组关联研究（GWAS），以确定与奈韦拉平超敏反应相关的不同临床表型的遗传易感因素。方法：在151例奈韦拉平过敏和182例耐受性HIV感染的马拉维成年人的发现队列中进行GWAS。在来自马拉维、乌干达和莫桑比克的116例病例和68例对照组中确定了信号的复制。在HLA-C*04：01阳性患者中确定与ERAP基因的相互作用。还对HLA-C*04：01进行了计算机模拟对接研究。结果：15个SNP与一种或多种超敏反应表型具有名义显著性（P < 1 × 10−5）。在SJS/TEN中观察到最有希望的信号，其中rs 5010528（HLA-C位点）接近全基因组显著性（P < 8.5 × 10−8），在发现和复制队列的荟萃分析中低于HLA全基因组显著性（P < 2.5 × 10−4）[OR 4.84（95%CI 2.71-8.61）]。rs 5010528是HLA-C*04：01携带的强代表：计算机对接显示B口袋中的两个残基（33和123）最可能是奈韦拉平相互作用物。HLA-C*04：01与ERAP 1之间没有相互作用，但与ERAP 2之间存在潜在的保护作用[P = 0.019，OR 0.43（95%CI 0.21-0.87）]。结论：HLA-C*04：01在撒哈拉以南非洲人中易患奈韦拉平诱导的SJS/TEN，但不易患其他超敏表型。这可能通过与HLA-C肽的B口袋结合来介导。这种风险是否受ERAP 2变异的调节需要进一步研究。
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.