Slow acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole hypersensitivity
Slow acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole hypersensitivity
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DOI：
10.1046/j.1365-2125.2003.01754.x
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发表时间：
2003-02-01
影响因子：
3.4
通讯作者：
Pirmohamed, M
中科院分区：
文献类型：
--
作者：
Alfirevic, A;Stalford, AC;Pirmohamed, M
目的探讨乙酰化酶状态在hiv阳性磺胺甲氧嘧啶（SMX）超敏患者中的作用，并探讨已报道的乙酰化酶表型与基因型的差异。方法采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对40例hiv阳性患者（其中32例为smx超敏患者）和26名健康志愿者进行基因分型，并以氨苯砜（50 mg）为探针对乙酰化状态进行表型分析。对NAT2外显子进行测序，检测到表型和基因分型之间的差异。我们的结果也与已发表的关于hiv阳性smx过敏患者缓慢乙酰化状态的研究进行了汇总。结果慢乙酰化基因型和表型频率在hiv阳性smx过敏患者和非过敏患者以及健康对照之间没有差异，这在已发表研究的荟萃分析中得到进一步证实（合并优势比2.25,95%置信区间0.45,11.17）。通过对整个NAT2外显子的测序，四名受试者的表型和基因型之间的不一致得到了解决，这揭示了罕见的突变，留下三名（9%）hiv阳性smx超敏感患者和一名（4%）健康志愿者继续表现出不一致。结论慢乙酰化表型或基因型不太可能使hiv阳性患者易患SMX超敏反应，尽管不能排除其轻微作用。表型-基因型差异部分是由于PCR方法未检测到所有罕见等位基因，并且可以通过对显示差异的患者的基因测序来规避。
Aims To test the role of acetylator status, and to investigate the reported discrepancy between acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole (SMX) hypersensitivity.Methods Forty HIV-positive patients (32 of whom were SMX-hypersensitive), and 26 healthy volunteers, were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, and phenotyped using dapsone (50 mg) as a probe, for acetylator status. Sequencing of the NAT2 exon was performed where discrepancy between phenotyping and genotyping was detected. Our results were also pooled with published studies addressing slow acetylator status in HIV-positive SMX-hypersensitive patients.Results Slow acetylator genotype and phenotype frequencies did not differ between HIV-positive SMX-hypersensitive and nonhypersensitive patients, and healthy controls, which was further confirmed in a meta-analysis of published studies (pooled odds ratio 2.25, 95% confidence interval 0.45, 11.17). Discordance between phenotype and genotype was resolved in four of the subjects by sequencing of the whole NAT2 exon, which revealed rare mutations, leaving three (9%) HIV-positive SMX-hypersensitive patients and one (4%) healthy volunteer who continued to demonstrate the discordance.Conclusions Slow acetylator phenotype or genotype is unlikely to predispose to SMX hypersensitivity in HIV-positive patients, although a minor role cannot be excluded. Phenotype-genotype discrepancies are partly due to nondetection of all rare alleles by PCR methodology, and can be circumvented by sequencing of the gene in patients showing a discrepancy.