甲状腺球蛋白基因外显子33单核苷酸多态性与Graves’病停药后复发的关系研究

Associations of thyroglobulin gene exon 33 single nucleotide polymorphism with the relapse of Graves’ disease after drug withdrawal

目的分析探讨甲状腺球蛋白基因外显子33单核苷酸多态性(E33SNP)与Graves’病(GD)的相关性;比较E33SNP与GD患者经过抗甲状腺药物(ATD)治疗缓解停药后复发的关系。方法按时间顺序选取2014年9月~2017年10月确诊的719例GD患者的临床资料进行分析,依据ATD治疗停药后复发的不同时间进行如下分组:GD患者停药后1年内复发者230例为A组;GD患者停药后1~2年内复发者253例为B组;GD患者停药后2年内未复发者236例为C组。另以同期健康体检者454例为对照组,均排除GD及其他自身免疫性甲状腺疾病。利用PCR测序法进行E33SNP单核苷酸多态性分型,比较GD组与对照组的基因型频率、等位基因频率;比较各GD组间基因型频率、等位基因频率及缓解停药后不同基因型的GD患者甲状腺功能指标(FT3,FT4,TSH)、甲状腺球蛋白(Tg)、促甲状腺激素受体抗体(TRAb)水平和相关临床资料,如眼征、甲状腺肿大程度的变化。结果 GD组与对照组的E33SNP基因型无统计学显著性差异(P>0.05),但GD组各亚组间E33SNP基因型差异有显著性(P<0.05或P<0.01)。对GD组的A,B,C 3个亚组间不同基因型患者各项甲状腺功能相关指标进行对比分析表明,不同基因型患者的TSH、FT3、FT4、Tg水平及甲状腺肿大程度无统计学差异(P>0.05),而TRAb的水平和眼征的发生率则具有统计学显著性(P<0.05或P<0.01)。结论甲状腺球蛋白基因外显子33单核苷酸多态性(E33SNP)与GD患者经过ATD治疗缓解停药后的复发存在相关关系;甲状腺球蛋白E33SNP CC型个体停药后的TRAb水平以及眼症的发生率明显增高,经ATD治疗停药后易复发,E33SNP TT型个体则呈现相反趋势,复发率低。

Objective The objective of the present study is to analyze the relationship between the polymorphism of exon 33 of thyroglobulin gene(E33 SNP) and the relapse of Graves’ disease(GD) after drug withdrawal.Methods A total of 719 patients with GD were enrolled in this study from September 2014 to October 2017.The clinical data were analyzed retrospectively.According to the time of relapse,the GD patients were divided into A,B and C subgroups.The A group contained 230 cases of relapse within 1 year,B group contained 253 cases of relapse 1~2 years after treatment and C group contained 236 cases without recurrence within 2 years.The healthy controls(454 cases) from our hospital physical examination center were selected.All subjects were genotyped.The genotypes of E33 SNP were identified by PCR.The genotype ratio of thyroglobulin between control group and observation group was comparatively analyzed.The levels of thyroidstimulating hormone(TSH),free triiodothyronine(FT3),free thyroxine(FT4),thyroglobulin(Tg) and thyrotropin receptor antibody(TRAb),ophthalmopathy and goiter size in A,B and C subgroups in different genotype GD patients were also investigated.Results The genotype of E33 SNP between GD group and control had no significant difference(P>0.05),but a significant difference between A,B,C subgroups was observed(P<0.05 or P<0.01).The relevant indicators of thyroid function in the patients with different genotypes showed that the levels of TSH,FT3,FT4 and Tg,and goiter size of the patients with different genotypes were no significant difference(P>0.05),while the TRAb levels and ophthalmopathy presented a significant difference(P<0.05 or P<0.01).Conclusion There was a relationship between the polymorphism of exon 33 of thyroglobulin gene and the relapse of Graves’ disease after drug withdrawal;The E33 SNP C/C genotype GD patients have a significantly higher TRAb level and ophthalmopathy rate than those in E33 SNP C/T and E33 SNP C/C genotype GD patients after ATD treatment,which were more likely to relapse.E33 SNP T/T genotype GD patients show a lower recurrence rate.