加纳人群中 MDR1、CYP3A4 和 CYP3A5 基因的遗传多态性：人类伊维菌素代谢改变的合理解释？
Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?
机构信息
School of Pharmacy, University of Portsmouth, St, Michael's Building, White Swan Road, Portsmouth PO1 2DT, UK.
出版信息
BMC Med Genet. 2010 Jul 14;11:111. doi: 10.1186/1471-2350-11-111.
BACKGROUND
Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies.
METHODS
Using PCR-RFLP, relevant polymorphic alleles of MDR1 and CYP3A4 genes were analysed in 204 randomly selected individuals and in 42 ivermectin treated patients.
RESULTS
We recorded significantly higher MDR1 (3435T) variant allele frequency in suboptimal responders (21%) than in patients who responded to treatment (12%) or the random population sample (11%). CYP3A41B, CYP3A53 and CYP3A56 alleles were detected at varied frequencies for the sampled Ghanaian population, responders and suboptimal responders to ivermectin. CYP3A51/CYP3A51 and CYP3A51/CYP3A5*3 genotypes were also found to be significantly different for responders and suboptimal responders. Haplotype (*1/*1/*3/*1) was determined to be significantly different between responders and suboptimal responders indicating a possible role of these haplotypes in treatment response with ivermectin.
CONCLUSION
A profile of pharmacogenetically relevant variants for MDR1, CYP3A4 and CYP3A5 genes has been generated for a random population of 204 Ghanaians to address the scarcity of data within indigenous African populations. In 42 patients treated with ivermectin, difference in MDR1 variant allele frequency was observed between suboptimal responders and responders.
背景
伊维菌素是多药耐药（MDR1）基因和细胞色素 P450（CYP）3A4 的底物，已成功用于加纳的盘尾丝虫病治疗。然而，一些患者在重复治疗后出现反应不佳的报道。宿主 MDR1 和 CYP3A 基因的多态性可能解释了伊维菌素观察到的反应不佳。我们对随机选择的加纳健康人群中的 MDR1 和 CYP3A 相关功能多态性进行了基因分型，并将数据与接受伊维菌素治疗的患者进行比较，以期探讨伊维菌素反应不佳与 MDR1 和 CYP3A 等位基因频率之间的关系。
方法
使用 PCR-RFLP，分析了 204 名随机选择的个体和 42 名接受伊维菌素治疗的患者的 MDR1 和 CYP3A4 基因的相关多态性等位基因。
结果
我们记录到反应不佳的患者（21%）的 MDR1（3435T）变体等位基因频率明显高于对治疗有反应的患者（12%）或随机人群样本（11%）。在所采样的加纳人群、对伊维菌素有反应的患者和反应不佳的患者中，检测到 CYP3A41B、CYP3A53 和 CYP3A56 等位基因的频率不同。还发现 CYP3A51/CYP3A51 和 CYP3A51/CYP3A5*3 基因型在反应良好的患者和反应不佳的患者之间存在显著差异。单倍型（*1/*1/*3/*1）在反应良好的患者和反应不佳的患者之间存在显著差异，表明这些单倍型可能在伊维菌素治疗反应中发挥作用。
结论
为了解决非洲本土人群数据稀缺的问题，我们为 204 名加纳随机人群生成了与 MDR1、CYP3A4 和 CYP3A5 基因相关的药理学相关变体图谱。在 42 名接受伊维菌素治疗的患者中，观察到反应不佳的患者和反应良好的患者之间 MDR1 变体等位基因频率存在差异。
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