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目的探讨细胞毒性T淋巴细胞相关抗原4(CTLA-4)基因多态性与甲巯咪唑(MMI)致山东地区汉族Graves病(GD)患者肝损害的相关性。方法研究对象选自2011年3月至2012年4月到青岛大学医学院附属医院内分泌科就诊或住院的GD患者(GD组)和同期到体检中心查体的健康人(健康对照组)。GD组分为3个亚组:单纯性GD组、MMI致肝损害组和甲亢性肝损害组。收集受试者外周非抗凝静脉血血凝块,提取基因组DNA,应用聚合酶链反应-限制性片段长度多态性技术测定CTLA-4基因第一外显子49位点和启动子区-318位点基因型,计算各组的基因型和等位基因频率。结果共收集到GD患者160例,其中单纯性GD组65例,男10例,女55例,平均年龄(40.4±14.4)岁;MMI致肝损害组40例,男11例,女29例,平均年龄(40.5±13.7)岁;甲亢性肝损害组55例,男9例,女46例,平均年龄(38.0±12.9)岁。健康对照组64例,其中男20例,女44例,平均年龄(40.7±10.7)岁。各组性别、年龄差异无统计学意义(P>0.05)。GD组和健康对照组CTLA-4基因第一外显子49位点AG+GG基因型频率分别为91.9%(147/160)和78.1%(50/64),G等位基因频率分别为74.4%(238/320)和59.4%(76/128),组间差异有统计学意义(χ2=8.153,P=0.004;χ2=6.259,P=0.012);启动子区-318位点的CT+TT基因型和T等位基因频率分布组间差异无统计学意义(P>0.05)。GD组的3个亚组之间两两比较,CTLA-4基因第一外显子49位点AG+GG基因型和G等位基因频率,启动子区-318位点CT+TT基因型和T等位基因频率差异均无统计学意义(均P>0.05)。结论 CTLA-4基因第一外显子49位点及启动子区-318位点多态性与山东地区汉族人群MMI所致肝损害无明显相关性,第一外显子49位点A/G多态性与GD的发生可能相关。
Objective To investigate the relationship between cytotoxic T lymphocyte associated antigen 4 (CTLA-4) gene polymorphisms and liver damage induced by methimazole (MMI) in Han patients with Graves’ disease (GD) in Shandong province. Methods Subjects were selected from GD patients (GD group) and healthy people (healthy control group) who went to the physical examination center for examination or hospitalization in Department of Endocrinology, Affiliated Hospital of Medical College of Qingdao University from March 2011 to April 2012. GD group was divided into three subgroups: pure GD group, MMI-induced liver damage group and hyperthyroidism liver damage group. The peripheral non-anticoagulant venous blood clots were collected and the genomic DNA was extracted. The location of the first exon 49 and the promoter region of CTLA-4 gene were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) 318 loci genotypes were calculated genotype and allele frequency of each group. Results A total of 160 GD patients were collected, including 65 cases of simple GD group, 10 males and 55 females, with an average age of (40.4 ± 14.4) years; MMI caused liver damage in 40 cases, 11 males and 29 females, The average age was (40.5 ± 13.7) years old; 55 cases of hyperthyroidism liver damage group, 9 males and 46 females, mean age (38.0 ± 12.9) years old. There were 64 healthy controls, 20 males and 44 females, with an average age of (40.7 ± 10.7) years. There was no significant difference in gender and age between groups (P> 0.05). The frequency of AG + GG genotype in CTLA-4 gene 49 locus was 91.9% (147/160) and 78.1% (50/64) in GD group and healthy control group, respectively. The frequencies of G allele were 74.4 (238/320) and 59.4% (76/128), respectively. The differences between the two groups were statistically significant (χ2 = 8.153, P = 0.004; χ2 = 6.259, P = 0.012) TT genotype and T allele frequency distribution between the two groups showed no significant difference (P> 0.05). GD group of three subgroups compared between pairs of CTLA-4 gene exon 49 49 locus AG + GG genotype and G allele frequency, promoter region -318 CT + TT genotype and T allele frequency differences were not statistically significant (all P> 0.05). Conclusion There is no significant correlation between CTLA-4 gene 49 exon 49 locus and promoter region -318 locus polymorphism and MMI-induced liver damage in Shandong Han population. The 49 locus A / G Polymorphism may be related to the occurrence of GD.