芳香烃受体信号通路相关基因多态性及mRNA在子宫内膜异位症发病中的相互作用

Interaction between aromatic hydrocarbon receptor signaling pathway-related gene polymorphism and its mRNA in the development of endometriosis

目的 探讨芳香烃受体(AhR)信号通路相关基因[AHR、AhR核异位蛋白(ARNT)、细胞色素P450 1A1(CYP1A1)、AhR阻遏蛋白(AhRR)、谷胱甘肽S转移酶1(GSTP1)、白细胞介素-1β(IL-1β)]多态性及mRNA在子宫内膜异位症(EMT)发病中的相互作用。方法 选择手术病理确诊为EMT的25例患者为病例组,25例非EMT患者为对照组。实时定量PCR法检测mRNA表达,定量PCR为基础的高分辨率熔解曲线(PCR-HRM)法检测基因多态性,采用单纯病例研究方法对基因-基因交互作用进行分析。结果 病例组中AhR mRNA、GSTP1 mRNA和IL-1βmRNA水平较对照组显著增高(P<0.01)。病例组中ARNT mRNA水平显著高于对照组(P<0.05)。携带CYP1A1 rs4646903 CC突变基因型的个体发生EMT的危险度是TT纯合野生型的7.5倍(95%CI:1.29~43.69),其他基因多态性的分布组间比较无显著差异(P>0.05)。CYP1A1 6235 T/C突变型与ARNT 522 G/C突变型(OR=9.33,95%CI:1.47~59.48)、GSTP1313 A/G突变型(OR=13.50,95%CI:1.34~135.98)存在协同作用。AHR 1661 G/A突变型与AHRR 565 C/G突变型存在协同作用(OR=13.50,95%CI:1.34~159.98),其他基因位点未见交互作用。结论 携带CYP1A1 rs4646903 CC基因型的个体发生EMT的风险性较高,CYP1A1 6235 T/C与ARNT 522 G/C突变型间的联合作用以及CYP1A1 6235 T/C与GSTP1313 A/G突变型间的联合作用与EMT的发病有关。

Objective To explore the interaction between aromatic hydrocarbon receptor(AhR)signaling pathway-related genes[AHR,AhR nuclear heterotopic protein(ARNT),cytochrome P450 1A1(CYP1A1),AhR repressor protein(AhRR),glutathione S-transferase 1(GSTP1),interleukin-1β(IL-1β)]polymorphism and messenger RNA(mRNA)in endometriosis pathogenesis(EMT).Methods A total of 25 patients with endometriosis confirmed by surgery and pathology were selected as case group(n=25),and 25 non-EMT patients were selected as control group(n=25).Gene polymorphism were detected by Polymerase Chain Reaction-High Resolution Melt(PCR-HRM)method,and expressions of mRNA were detected by real-time quantitative PCR in both groups.The gene-gene interactions were analyzed based on the simple-case-study method.Results The levels of AhR,GSTP1 and IL-1βmRNAs in case group were significantly higher than those in control group(P<0.01).The level of ARNT mRNA in case group increased significantly when compared with that in control group(P<0.05).The risk of EMT in patients with CYP1A1 rs4646903 CC mutation genotype was 7.5 times higher than patients with homozygous wild genotype TT(95%CI:1.29 to 43.69),and there were no significant differences in frequencies of other genotypes between case group and control group(P>0.05).The synergistic role of mutated CYP1A1 6235 T/C and mutated ARNT 522 G/C gene increased the risk of endometriosis(OR=9.33,95%CI:1.47 to 59.48),and the risk of disease also increased when combined with mutated CYP1A1 6235 T/C and mutated GSTP1313 A/G gene(OR=13.50,95%CI:1.34 to 135.98).Moreover,combined with mutated AHR 1661 G/A and AHRR 565 C/G appeared to cause a significant increase in endometriosis(OR=13.50,95%CI:1.34 to 159.98).No interaction was found at other loci.Conclusion Patients with CYP1A1 rs4646903 CC gene has a high risk in developing endometriosis.The combined mutated genotypes(CYP1A1 6235 T/C and ARNT 522 G/C,CYP1A1 6235 T/C and GSTP1313 A/G)might be related with susceptibility to endometriosis.