Polymorphisms in drug metabolism genes predict the risk of refractory myasthenia gravis.
Polymorphisms in drug metabolism genes predict the risk of refractory myasthenia gravis.
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药物代谢基因多态性预测难治性重症肌无力的风险
DOI：
10.21037/atm-22-2543
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发表时间：
2022-11
影响因子：
--
通讯作者：
Bu, Bitao
中科院分区：
文献类型：
--
作者：
Zhang, Qing;Ge, Huizhen;Gui, Mengcui;Yang, Mengge;Bi, Zhuajin;Ma, Xue;Gu, Zhongya;Peng, Shu;Chen, Tao;Bu, Bitao
背景近10%-20%的重症肌无力（MG）患者因不明原因而对常规治疗无效。本研究旨在探讨药物代谢基因多态性与难治性MG的关系。方法回顾性分析同济医院收治的131例MG患者，其中难治组33例，非难治组98例。采用改进的多重连接检测反应（iMLDR）对13个多态性位点进行基因分型（NR3C1 rs17209237，rs9324921; FKBP 5 rs1360780，rs4713904，rs9296158; HSP 90AA 1 rs10873531，rs2298877，rs7160651; MDR 1 rs1045642，rs1128503，rs2032582; CYP 3A 4 rs 2242480;和CYP 3A 5 rs776746）。我们应用多变量logistic回归分析来研究难治性MG与核苷酸多态性之间的关系。广义多因素降维（GMDR）被用来研究基因-基因相互作用。结果HSP 90 AA 1 rs7160651基因CC型与难治性MG的发病风险相关性高于CT基因型[OR =0.26; P=0.041]和CT + TT基因型[优势模型，OR =0.24; P=0.022]。对于CYP 3A 5 rs776746，AA基因型与难治性MG相关，而AG基因型（OR =0.11; P=0.017）、GG基因型（OR =0.18; P=0.033）和AG + GG基因型（显性模型，OR =0.16; P=0.020）与难治性MG相关。HSP 90 AA 1 rs 10873531、rs 2298877、rs7160651的CAT单倍型在难治性患者中的频率较低（OR =0.33; P=0.044）。没有观察到显著的基因-基因相互作用。结论HSP 90 AA 1 rs7160651和CYP 3A 5 rs776746与难治性MG相关。进一步的研究是必要的，以确认结果，并调查使用多态性的治疗个体化。
Background Nearly 10% to 20% of myasthenia gravis (MG) patients are refractory to conventional treatment for unclear reasons. The study aimed to explore the relationship between drug metabolism gene polymorphisms and refractory MG. Methods One hundred and thirty-one MG patients (33 in the refractory group; 98 in the non-refractory group) admitted to Tongji Hospital were included in this retrospective study. Improved multiplex ligation detection reaction (iMLDR) was used to genotype 13 polymorphisms (NR3C1 rs17209237, rs9324921; FKBP5 rs1360780, rs4713904, rs9296158; HSP90AA1 rs10873531, rs2298877, rs7160651; MDR1 rs1045642, rs1128503, rs2032582; CYP3A4 rs2242480; and CYP3A5 rs776746). We applied multivariable logistic regression to investigate the association between refractory MG and nucleotide polymorphisms. Generalized multifactor dimensionality reduction (GMDR) was used to examine gene-gene interactions. Results CC genotype of HSP90AA1 rs7160651 was associated with the increased risk of refractory MG than CT genotype [odds ratio (OR) =0.26; P=0.041] and CT + TT genotype (dominant model, OR =0.24; P=0.022). For CYP3A5 rs776746, AA genotype was associated with refractory MG compared with AG genotype (OR =0.11; P=0.017), GG genotype (OR =0.18; P=0.033), and AG + GG genotype (dominant model, OR =0.16; P=0.020). The frequency of CAT haplotype of HSP90AA1 rs10873531, rs2298877, rs7160651 was less common in refractory patients (OR =0.33; P=0.044). No significant gene-gene interactions were observed. Conclusions HSP90AA1 rs7160651 and CYP3A5 rs776746 were significantly associated with refractory MG. Further studies are warranted to confirm the results and investigate the use of polymorphisms for treatment individualization.
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