Methylation levels of the TNFA gene are different between Graves’ and Hashimoto’s diseases and influenced by the TNFA polymorphism
Methylation levels of the TNFA gene are different between Graves’ and Hashimoto’s diseases and influenced by the TNFA polymorphism
复制标题
格雷夫斯病和桥本病的 TNFA 基因甲基化水平不同，并受到 TNFA 多态性的影响
DOI：
10.1080/08916934.2018.1448078
复制
发表时间：
2018
期刊：
影响因子：
3.5
通讯作者：
Iwatani Yoshinori
中科院分区：
文献类型：
--
作者：
Morita Emi;Watanabe Mikio;Inoue Naoya;Hashimoto Hidemi;Haga Emi;Hidaka Yoh;Iwatani Yoshinori
Graves病(GD)和桥本病(HD)是自身免疫性甲状腺疾病(AITDS)的不同病理类型。然而，这些疾病之间的表观遗传学差异尚未阐明。DNA甲基化是主要的表观遗传修饰之一，反映了环境对基因表达的影响。在本研究中，我们利用焦磷酸测序技术检测了肿瘤坏死因子基因启动子上6个CpG位点的甲基化状态，并结合该基因的功能多态(−1031 T/C和 +123 C/T)进行分析，以阐明基因甲基化在AITDS预后中的作用。我们用焦磷酸测序技术检测了52例GD患者、60例HD患者和29例健康对照的甲基化模式。此外，我们还采用限制性片段长度多态性(RFLP)方法对163例GD患者、152例HD患者和94例健康对照的基因多态性进行了分型。−72CpG低甲基化(≤11.9%)、−49CpG低甲基化(≤15.5%)和−38CpG低甲基化(≤8.9%)的受试者在高浓度组(α(≥0.134 pg/m L)均显著增加。GD患者−72CpG位点甲基化水平(10.7 ± 4.9%)显著高于正常对照组(6.8 ± 3.9%)。缓解期GD患者−49和−38位点甲基化水平(分别为20.5 ± 9.5%和17.6 ± 8.0%)显著高于正常对照组(分别为13.0 ± 7.6%和7.9 ± 7.3%)。肿瘤坏死因子− 1031C携带者(CT + CC)的频率与肿瘤坏死因子-α的产生有关，且在GD组(35.0%)和HD组(39.5%)明显高于对照组(19.1%)。在TNFA− 1031C携带者(CT + CC)中，GD患者−72CpG位点甲基化水平(11.5 ± 5.7%)显著高于HD患者(6.0 ± 3.4%)。但在TT基因携带者中，GD和HD之间无明显差异。我们的研究结果提示，TnFA3基因中CpG位点的甲基化水平可能与AITDS中GD和HD的差异有关，并可能受TNFA1基因多态性的影响。
Graves’ disease (GD) and Hashimoto’s disease (HD) are different pathological types of autoimmune thyroid diseases (AITDs). However, the epigenetic differences between these diseases have not been elucidated. DNA methylation is one of the primary epigenetic modifications that reflect environmental influences on gene expression. In this study, we evaluated the methylation status of six CpG sites in theTNFApromoter using pyrosequencing and analyzed the data in combination with functional polymorphisms (−1031 T/C and +123 C/T) in theTNFAgene to clarify the role of gene methylation on the prognosis of AITDs. We examined the methylation pattern in 52 patients with GD, 60 patients with HD, and 29 healthy controls by pyrosequencing. Additionally, we also genotyped the polymorphisms from 163 patients with GD, 152 patients with HD, and 94 healthy controls using the restriction fragment length polymorphism (RFLP) method. Each proportion of subjects with low methylation of the −72 CpG site (≤11.9%), low methylation of the −49 CpG site (≤15.5%), and low methylation of the −38 CpG site (≤8.9%) was significantly increased in the groups with high concentration of TNF-α (≥0.134 pg/mL). The methylation level of the −72 CpG site was significantly higher in GD cases (10.7 ± 4.9%) than in healthy controls (6.8 ± 3.9%). The methylation level of the −49 and −38 CpG sites were significantly higher in patients with GD in remission (20.5 ± 9.5%, 17.6 ± 8.0%, respectively) than in healthy controls (13.0 ± 7.6%, 7.9 ± 7.3%, respectively). The frequency of theTNFA− 1031C carrier (CT + CC) is correlated with higher TNF-α production and was significantly higher in GD (35.0%) and HD (39.5%) cases than in controls (19.1%). In the subjects with theTNFA− 1031C carrier (CT + CC), the methylation level of the −72 CpG site was significantly higher in GD (11.5 ± 5.7%) than in HD (6.0 ± 3.4%). However, there was no difference between GD and HD in patients with the TT genotype. Cumulatively, our data indicate the methylation levels of CpG sites in theTNFAgene may be related to the difference between GD and HD in AITDs and may be influenced by theTNFAgene polymorphism.