CAJ | 학술논문

目的：了解中国汉族结核病患者 N-乙酰基转移酶（NAT2）基因型与异烟肼引起的药物性肝损伤及与抗结核疗效的关系。方法初治结核病患者108例。采用 PCR 直接测序法对 NAT2基因7个单核苷酸多态性位点分析比对，判定 NAT2基因型。分析基因型与药物性肝损伤的关系，比较基因型与抗结核疗效的关系。统计学处理采用χ2检验。结果108例结核病患者中，中间代谢型59例（54．63％），快代谢型36例（33．33％），慢代谢型11例（10．19％），超快代谢型2例（1．85％）。20例药物性肝损伤患者中快代谢型2例，慢代谢型5例，中间代谢型13例。快代谢型患者发生药物性肝损伤可能性较低（OR ＝0．176，95％CI ：0．038～0．809，P ＝0．014），慢代谢型患者易发生药物性肝损伤（OR ＝4．556，95％CI ：1．231～16．854，P ＝0．044）。NAT2*4／*6A 基因型（OR ＝7．741，95％CI ：2．653～22．586，P ＜0．01）和 NAT2*6A／*6A 基因型（OR＝15．353，95％CI ：1．506～156．552，P ＝0．020）患者易发生药物性肝损伤，NAT2*4／*4型患者则不易发生药物性肝损伤（OR ＝0．176，95％CI ：0．038～0．809，P ＝0．014）。58例痰菌阳性的患者，治疗2个月后仍痰菌阳性12例，其中快代谢型患者8例，疗效差（OR＝7．200，95％CI ：1．794～28．900，P ＝0．008）。结论中国汉族结核病患者中 NAT2基因型以中间代谢型为主。NAT2慢代谢型发生药物性肝损伤的风险较高。NAT2*6A 为药物性肝损伤高风险等位基因，而 NAT2*4／*4则可能为保护性基因型。快代谢型患者早期的疗效较差。
목적：료해중국한족결핵병환자 N-을선기전이매（NAT2）기인형여이연정인기적약물성간손상급여항결핵료효적관계。방법초치결핵병환자108례。채용 PCR 직접측서법대 NAT2기인7개단핵감산다태성위점분석비대，판정 NAT2기인형。분석기인형여약물성간손상적관계，비교기인형여항결핵료효적관계。통계학처리채용χ2검험。결과108례결핵병환자중，중간대사형59례（54．63％），쾌대사형36례（33．33％），만대사형11례（10．19％），초쾌대사형2례（1．85％）。20례약물성간손상환자중쾌대사형2례，만대사형5례，중간대사형13례。쾌대사형환자발생약물성간손상가능성교저（OR ＝0．176，95％CI ：0．038～0．809，P ＝0．014），만대사형환자역발생약물성간손상（OR ＝4．556，95％CI ：1．231～16．854，P ＝0．044）。NAT2*4／*6A 기인형（OR ＝7．741，95％CI ：2．653～22．586，P ＜0．01）화 NAT2*6A／*6A 기인형（OR＝15．353，95％CI ：1．506～156．552，P ＝0．020）환자역발생약물성간손상，NAT2*4／*4형환자칙불역발생약물성간손상（OR ＝0．176，95％CI ：0．038～0．809，P ＝0．014）。58례담균양성적환자，치료2개월후잉담균양성12례，기중쾌대사형환자8례，료효차（OR＝7．200，95％CI ：1．794～28．900，P ＝0．008）。결론중국한족결핵병환자중 NAT2기인형이중간대사형위주。NAT2만대사형발생약물성간손상적풍험교고。NAT2*6A 위약물성간손상고풍험등위기인，이 NAT2*4／*4칙가능위보호성기인형。쾌대사형환자조기적료효교차。
Objective To investigate the association of the polymorphism of the N-acetyltransferase 2 (NAT2 )gene with isoniazid-induced hepatotoxicity and anti-tuberculous treatment efficacy in Chinese Han patients with tuberculosis(TB).Methods A total of 108 TB patients who received initial anti-TB treatment were followed up prospectively.A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 gene.Associations between NAT2 genotype and isoniazid-induced hepatitis/early treatment were analyzed.Chi-square test was used for statistical analysis. Results Among the 108 TB patients, intermediate-acetylators (IA ) was the most frequent NAT2 genotype with the proportion of 54.63%(59/108).The proportion of rapid-acetylators(RA)was 33.33%(36/108),slow-acetylators (SA)was 10.19%(11/108)and super-rapid acetylators was 1 .85 % (2/108). Among the 20 patients who developed drug-induced hepatitis,2 were RA,5 were SA and 13 were IA. Regarding NAT2 genotype,RA patients had a lower incidence of hepatotoxicity (OR =0.176,95 %CI :0.038-0.809,P =0.014)and SA patients were more likely to developed drug-induced hepatic injury (OR=4.556,95 %CI :1 .231 -16.854,P =0.044 ).Statistical analysis revealed that the frequency of variant diplotypes,NAT2*4/*6A (OR=7.741 ,95 %CI :2.653-22.586,P <0.01 )and NAT2 *6A/*6A (OR=15 .353,95 %CI :1 .506 -156.552,P =0.020)were significantly increased in TB patients with hepatotoxicity.NAT2 *4/*4 was less likely to developed hepatic injury (OR =0.176,95 %CI :0.038-0.809,P =0.014).Among the 58 culture-positive patients,12(31 .03%)were persistent culture positive after 2 months standard therapy.Early treatment failure was observed with significantly higher incidence rate in RA than other genotypes (OR = 7.200, 95 % CI :1 .794-28.900, P = 0.008). Conclusions In Chinese Han TB patients,IA is the most frequent NAT2 genotype.The SA status of NAT2 is a risk factor of isoniazid-induced hepatotoxicity.The diplotype of NAT2 *6A has clearly high risk of isoniazid-induced hepatotoxicity.In contrast,NAT2 * 4/* 4 is protective diplotype.RA is associated with early treatment failure in culture-positive patients.