抗甲状腺药物致白细胞减少易感性与HLA-DRB1基因多态性及ANCA的关联性

Association of HLA-DRB1 allele polymorphism and ANCA with the susceptibility to antithyroid drug-induced leucocytopenia in patients with Graves＇ disease

目的 研究安徽地区汉族Graves病患者使用抗甲状腺药物（ATD）致白细胞减少的易感性与HLA-DRB1基因多态性及抗中性粒细胞胞浆抗体（ANCA）的相关性.方法 采用聚合酶链反应-序列特异性引物方法（PCR-SSP）检测76例ATD致白细胞减少的Graves病患者、98例ATD治疗后白细胞正常患者和230名健康对照者的等位基因HLA-DRB1＊ 08032、DRBI＊ 1501、DRB1＊0901的频率.采用间接免疫荧光法（IIF）检测白细胞减少组和白细胞正常组Graves病患者的血清ANCA阳性率.结果 （1）与健康对照组及细胞正常组比较,白细胞减少组患者等位基因DRB1 ＊ 08032、DRB1＊1501频率明显增加（OR分别为3.06,1.77,4.03和2.28,均P＜0.05）,DRB1＊ 0901频率明显减低（OR为0.33和0.43,P＜0.05）.（2）与甲巯咪唑治疗后白细胞正常组患者比较,甲巯咪唑致白细胞减少组患者血清ANCA阳性率明显增加（x2 =4.878,P＜0.05）.（3）与未携带等位基因DRB1＊08032和DRB1＊1501的患者比较,携带者血清中ANCA阳性率明显增加（x2为5.682,5.429,4.009和4.549,均P＜0.05）.结论 等位基因HLA-DRB1＊08032、HLA-DRB1＊1501可能是安徽地区汉族人ATD致白细胞减少的易感基因；HLA-DRB1＊0901可能是其保护基因或抗性基因.免疫反应可能参与了ATD致白细胞减少的发生.免疫反应的发生可能存在遗传易感性.

Objective To investigate the relationship of HLA-DRB1 allele polymorphism and antineutropil cytoplasmic antibody （ ANCA ） with the susceptibility to antithyroid drug （ ATD ） -induced leucocytopenia in the patients with Graves＇ disease （GD） in Anhui Han Chinese.Methods The HLA-DRB1 ＊ 08032,DRB1 ＊ 1501,and DRB1 ＊ 0901 allele frequencies were determined by the polymerase chain reaction-based sequence-specific primer （PCR-SSP） method in 76 patients with Graves＇ disease who had ATD-induced leucocytopenia and 98 patients with Graves＇ disease treated with ATD,who were free from leucocytopenia.The other230 healthy subjects served as controls.Indirect immunofluorescence assay （IIF） was used to detect ANCA positive rate.Result （ 1 ） Compared with the controls and the GD patients without leucocytopenia,the allele frequencies ofDRB1 ＊ 08032 and DRB1 ＊ 1501 in patients with ATD-induced leucocytopenia were significantly increased （ OR were 3.06,1.77,4.03,and 2.28,all P〈0.05）,while that of HLA-DRB1 ＊ 0901 was decreased （ OR were 0.33 and 0.43,both P〈0.05 ）.（2）The ANCA frequencies were significantly increased in the GD patients with methimazole-induced leucocytopenia compared with those without leucocytopenia （x2 =4.878,P〈0.05 ）.（ 3 ） Compared with the GD patients not carrying DRB1 ＊ 08032,DRB1 ＊ 1501,and DRB1 ＊ 0901 alleles,the ANCA positive rates were significantly increased in the GD patients carrying these alleles（x2 were 5.682,5.429,4.009,and 4.549,all P〈0.05）.Conclusions The DRB1 ＊ 08032 and HLA-DRB1 ＊ 1501 alleles may be susceptible to ATD-induced leucocytopenia in Anhui Hans,while HLA-DRB1 ＊ 0901 alleles may be protective or resistant gene.Immune response may be involved in the development of leucocytopenia.The occurrence of immune response is based on the genetic susceptibility.