目的:HIF-1α基因多态性,包括rs11549465,rs11549467,rs1957757和rs10873142,引起肝细胞损伤或肺部疾病。这项研究的目的是分析HIF-1α基因位点的多态性及其启动子区域的CpG岛甲基化与抗结核药物诱导的肝损伤(ADSI)风险之间的关系。
方法:286例肺结核合并ADLI患者(病例组)和286例无肝损伤的肺结核患者(对照组)一对一匹配,在2019年7月至2020年7月招募的1728名结核病患者中。使用PCR-RFLP技术确认HIF-1α基因的四个基因座的基因分型。使用MSP方法测量HIF-1α基因的甲基化。风险因素的比较,病例组和对照组之间的HIF-1α基因型和甲基化状态均通过单因素和多因素条件logistic回归得到。
结论:单因素分析显示,病例组rs1957757突变基因型和CpG岛甲基化频率明显高于对照组(均P<0.001)。相比之下,两组之间其他三个基因座的突变基因型频率没有统计学差异(分别为p=0.21,p=0.12和p=0.55)。Further,多变量分析表明CpG岛被甲基化,rs1957757位点的突变基因型与ADLI的高风险独立相关,调整后的OR(95CI)达到1.92(1.32-2.63)和2.01(1.32-2.83),分别。此外,以rs1957757位点野生基因型和未甲基化的CpG岛作为参照组,突变基因型和CpG岛甲基化增加了ADLI的风险,ADLI的概率可以达到参考组的4.73倍。
结论:这是HIF-1α基因多态性和CpG岛甲基化与ADLI危险分层的相关性的首次证明。在HIF-1α基因启动子区域甲基化的CpG岛与其rs1957757基因座突变基因型之间的相互作用与较高的ADLI风险相关。
OBJECTIVE: HIF-1α gene polymorphisms, including rs11549465, rs11549467, rs1957757 and rs10873142, cause liver cell damage or pulmonary disease. The aim of this study was to analyse the association between the polymorphisms of the loci of the HIF-1α gene and its CpG island methylation in the promoter region with the risk of anti-tuberculosis drug-induced liver injury (ADLI).
METHODS: 286 patients with tuberculosis (TB) and ADLI (
case group) and 286 patients with TB but without liver injury (control group) were matched one-to-one, among the 1728 TB patients recruited from July 2019 to July 2020. Genotyping of the four loci of the HIF-1α gene was confirmed using PCR-RFLP technology. Methylation of the HIF-1α gene was measured using the MSP method. The comparison of risk factors, HIF-1α genotype and methylation status between the
case group and the control group was all achieved through univariate and multivariate conditional logistic regression.
CONCLUSIONS: Univariate analysis showed that the frequency of rs1957757 mutation genotype and CpG island methylation was significantly higher in the
case group than in the control group (P<0.001, all). In contrast, there was no statistical difference in the frequency of mutated genotypes at the other three loci between the two groups (p = 0.21, p = 0.12 and p = 0.55, respectively). Further, multivariate analysis showed that CpG islands were methylated, the mutation genotype of the rs1957757 locus was independently associated with the high risk of ADLI, and the adjusted OR (95%CI) reached 1.92 (1.32-2.63) and 2.01 (1.32-2.83), respectively. Furthermore, taking the rs1957757 locus wild genotype and CpG islands without methylation as the reference group, the mutation genotype and CpG island methylation increased the risk of ADLI, and the probability of ADLI could reach 4.73 times that of the reference group.
CONCLUSIONS: This is the first demonstration of the association of HIF-1α gene polymorphism and CpG island methylation with ADLI risk stratification. The interaction between CpG islands methylated in the promoter region of the HIF-1α gene and its rs1957757 locus mutant genotype was associated with a higher risk of ADLI.