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目的抗甲状腺药物(antithyroid drug,ATD)是治疗Graves病(Graves disease,GD)的主要方法之一,但治疗中常见不良反应为白细胞减少,并可由此导致严重后果。ATD导致白细胞减少、缺乏的发病机制仍不清楚,可能与遗传易感性,用药剂量等因素有关。本实验旨在探讨青岛地区汉族GD患者CTLA-4基因启动子-3l8位点C/T多态性与抗甲状腺药物(ATD)治疗GD导致白细胞减少的相关性。方法应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术测定159例GD患者(其中ATD导致白细胞减少组73例,ATD治疗后白细胞正常组86例,初发甲亢合并白细胞减少组52例),74例非GD白细胞减少患者和85例正常对照者CTLA-4基因启动子-318位点的基因型,并计算其基因型和等位基因频率。结果 CTLA-4基因启动子-318位点的基因型和等位基因频率:①在GD组和对照组中分布无显著性差异(χ2=0.60,P=0.74;χ2=0.06,P=0.80)。②ATD导致白细胞减少组与ATD治疗前后白细胞正常组的分布有显著性差异(χ2=7.28,P=0.03;χ2=4.05,P=0.04)。ATD导致白细胞减少组CT+TT基因型频率明显高于ATD治疗后白细胞正常组(26.0%vs11.6%)。T等位基因频率明显高于ATD治疗后白细胞正常组(13.0%vs6.4%)③ATD导致白细胞减少组与GD合并白细胞减少组分布无显著性差异(χ2=2.91,P=0.09;χ2=2.57,P=0.11)。结论 CTLA-4基因启动子-318位点多态性与ATD治疗导致的白细胞减少相关,与青岛地区汉族人群GD的发病无关。
Objective Antithyroid drug (ATD) is one of the main methods for the treatment of Graves disease (GD). However, common adverse reactions in treatment are leukopenia and can lead to serious consequences. ATD lead to leukopenia, the lack of pathogenesis is still not clear, may be related to genetic susceptibility, dosage and other factors. The purpose of this study was to investigate the relationship between CTLA-4 gene promoter -318 locus C / T polymorphism and anti-thyroid drug (ATD) treatment for GD-induced leukopenia in GD Han patients. Methods 159 patients with GD were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Among them, 73 patients with leukopenia caused by ATD, 86 patients with normal leukocyte after ATD treatment, and primary hypothyroidism with leukopenia (N = 52). 74 genotypes of CTLA-4 gene promoter-318 site in 74 patients with non-GD leukemia and 85 normal controls were analyzed. The genotype and allele frequency of CTLA-4 gene were calculated. Results Genotype and allele frequency of CTLA-4 gene promoter-318 site: ① There was no significant difference in GD and control groups (χ2 = 0.60, P = 0.74; χ2 = 0.06, P = 0.80) . There were significant differences in the distribution of leukocytes between ATD-induced leukopenia group and before and after ATD treatment (χ2 = 7.28, P = 0.03; χ2 = 4.05, P = 0.04). The frequency of CT + TT genotype in leukopenia group was significantly higher than that in ATD-treated leukocyte group (26.0% vs11.6%) after ATD. The frequency of T allele was significantly higher than that of normal leukocytes after ATD treatment (13.0% vs 6.4%). ③ There was no significant difference in ATD between leukopenia group and GD group (χ2 = 2.91, P = 0.09; χ2 = 2.57 , P = 0.11). Conclusion The polymorphism of CTLA-4 promoter -318 locus is associated with leukopenia induced by ATD, but not with the incidence of GD in Han nationality in Qingdao.