ABCB1 gene polymorphism associated with clinical factors can predict drug-resistant tuberculosis
ABCB1 gene polymorphism associated with clinical factors can predict drug-resistant tuberculosis
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DOI：
10.1042/cs20170277
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发表时间：
2017-08-01
期刊：
影响因子：
6
通讯作者：
de Castro, Liane
中科院分区：
文献类型：
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作者：
Pontual, Yasmin;Pacheco, Vanessa S. S.;de Castro, Liane
编码P-糖蛋白（一种跨膜药物外排泵）的ABCB 1基因的多态性与耐药性有关，已被广泛研究。然而，它们与结核病（TB）患者利福平和乙胺丁醇耐药的关系尚不清楚。从218名患者中获得c.1236C > T（rs 1128503）、c.2677G > T/A（rs 2032582）和c.3435C > T（rs 1045642）的基因型/等位基因/单倍型频率。根据细菌培养和药敏试验结果，选择80例利福平和（或）乙胺丁醇耐药的患者作为病例组，138例患者作为对照组。年龄< 18岁和HIV血清学检测阳性的患者被排除在外。ABCB 1多态性采用PCR直接测序法和限制性片段长度多态性（RFLP）测定。构建诺模图来模拟抗结核药物耐药概率的组合预测，其中因子包括基因型c。1236 C> T（rs 1128503）（P=0.02）、临床形式（P=0.03）、既往治疗（P=0.01）和皮肤颜色（P=0.03），导致高达90%的机会发生抗结核药物耐药性。考虑到基因型分析，CT（rs 1128503）表现出抗结核药物耐药性的机会增加（比值比（OR）：2.34，P=0.02），而乙胺丁醇耐药分析显示与罕见的A等位基因相关（rs 2032582）（OR：12.91，P=0.01）、TTC单倍型（OR：5.83，P=0.05）和任何含有罕见A等位基因的单倍型（OR：7.17，P=0.04）。ABCB 1基因多态性与其他危险因素相关，有助于抗结核药物耐药，主要是乙胺丁醇。本研究中描述的列线图的使用有助于在开始TB治疗之前做出临床决策。
Polymorphism in the ABCB1 gene encoding P-glycoprotein, a transmembrane drug efflux pump, contributes to drug resistance and has been widely studied. However, their association with rifampicin and ethambutol resistance in tuberculosis (TB) patients is still unclear. Genotype/allele/haplotype frequencies in c.1236C > T (rs1128503), c.2677G > T/A (rs2032582), and c.3435C > T (rs1045642) were obtained from 218 patients. Of these, 80 patients with rifampicin and/or ethambutol resistance were selected as the case group and 138 patients were selected for the control group through the results of their culture and drug-sensitive tests. Patients aged < 18 years and HIV-positive serologic tests were excluded. ABCB1 polymorphisms were determined using a PCR direct-sequencing approach, and restriction fragment length polymorphism (RFLP). A nomogram was constructed to simulate a combined prediction of the probability of anti-TB drug resistance, with factors including genotype c. 1236C > T (rs1128503) (P=0.02), clinical form (P=0.03), previous treatment (P=0.01), and skin color (P=0.03), contributing up to 90% chance of developing anti-TB drug resistance. Considering genotype analyses, CT (rs1128503) demonstrated an increased chance of anti-TB drug resistance (odds ratio (OR): 2.34, P=0.02), while the analyses for ethambutol resistance revealed an association with a rare A allele (rs2032582) (OR: 12.91, P=0.01), the haplotype TTC (OR: 5.83, P=0.05), and any haplotype containing the rare A allele (OR: 7.17, P=0.04). ABCB1 gene polymorphisms in association with others risk factors contribute to anti-TB drug resistance, mainly ethambutol. The use of the nomogram described in the present study could contribute to clinical decision-making prior to starting TB treatment.