目的通过检测结核病患者药物代谢酶N-乙酰基转移酶2(N-acetyltransferase 2,NAT2)与妊娠X受体基因(Pregnane X receptor,PXR)启动子区rs3814055的基因多态性,根据结果进行风险分型,并验证对发生结核药物性肝损伤的预测价值。方法将382...目的通过检测结核病患者药物代谢酶N-乙酰基转移酶2(N-acetyltransferase 2,NAT2)与妊娠X受体基因(Pregnane X receptor,PXR)启动子区rs3814055的基因多态性,根据结果进行风险分型,并验证对发生结核药物性肝损伤的预测价值。方法将382例采用一线HREZ抗结核方案的敏感性结核患者在治疗前对NAT2及rs3814055的多态性位点进行测序分析,并进行风险分型,按结果分为高、中、低风险组,通过观察其实际发生肝损伤情况进行对比分析,以此验证风险类型与ATDILT间的相关性。结果低风险组患者185名,发生ATDILT的比例为15.7%(29/185);中风险组患者132名,发生ATDILT的比例为28.0%(37/132);高风险组患者65名,发生ATDILT的比例为32.3%(21/65)。高风险组与低风险组相比,发生肝损伤的相对危险度为1.909(95%CI为1.258~2.898);中风险组与低风险组相比,发生肝损伤的相对危险度为1.481(95%CI为1.135~1.933),且均有统计学意义(χ^(2)=8.316,P<0.01;χ^(2)=7.133,P<0.01)。高、中风险组间无显著性差异。结果显示患者性别与年龄对ATDILT发生率无显著性影响。结论基于NAT2及rs3814055多态性的联合检测的风险分型可用来预测结核病患者药物性肝损伤的发生。展开更多
AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treat...AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.展开更多
文摘目的通过检测结核病患者药物代谢酶N-乙酰基转移酶2(N-acetyltransferase 2,NAT2)与妊娠X受体基因(Pregnane X receptor,PXR)启动子区rs3814055的基因多态性,根据结果进行风险分型,并验证对发生结核药物性肝损伤的预测价值。方法将382例采用一线HREZ抗结核方案的敏感性结核患者在治疗前对NAT2及rs3814055的多态性位点进行测序分析,并进行风险分型,按结果分为高、中、低风险组,通过观察其实际发生肝损伤情况进行对比分析,以此验证风险类型与ATDILT间的相关性。结果低风险组患者185名,发生ATDILT的比例为15.7%(29/185);中风险组患者132名,发生ATDILT的比例为28.0%(37/132);高风险组患者65名,发生ATDILT的比例为32.3%(21/65)。高风险组与低风险组相比,发生肝损伤的相对危险度为1.909(95%CI为1.258~2.898);中风险组与低风险组相比,发生肝损伤的相对危险度为1.481(95%CI为1.135~1.933),且均有统计学意义(χ^(2)=8.316,P<0.01;χ^(2)=7.133,P<0.01)。高、中风险组间无显著性差异。结果显示患者性别与年龄对ATDILT发生率无显著性影响。结论基于NAT2及rs3814055多态性的联合检测的风险分型可用来预测结核病患者药物性肝损伤的发生。
基金by Grant-in-Aid for Scientif ic Research (Category B, No. 18390168) for K Tsukamoto by the Ministry of Education, Culture, Sports, Science and Technology of Japan
文摘AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.
