抗甲状腺药物致白细胞减少症的易感性与HLA-DRB1基因多态性及ANCA相关性研究
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摘要
目的研究安徽地区汉族Graves病(GD)患者使用抗甲状腺药物(ATD)致白细胞减少的易感性与等位基因HLA-DRB1多态性及抗中性粒细胞胞浆抗体(ANCA)的相关性。
方法①采用聚合酶链反应-序列特异性引物(PCR-SSP)方法检测76例使用ATD致白细胞减少的患者、98例使用ATD白细胞正常患者和230名健康对照组的HLA-DRB1*08032,DRB1*1501,DRB1*0901的等位基因频率。②采用间接免疫荧光法( IIF)检测76例ATD致白细胞减少的患者、98例使用ATD白细胞正常患者血清中的ANCA。阳性者则进一步用应用斑点法测定抗髓过氧化物酶(MPO)抗体及抗蛋白酶3(PR3)抗体。
结果①与健康对照组比较,白细胞减少组DRB1*08032,DRB1*1501频率明显增加(p=0.00,OR=3.06;p=0.042,OR=1.77),DRB1*0901的频率明显减低(p=0.01,OR=0.33)。②与白细胞正常组比较,白细胞减少组DRB1*08032和DRB1*1501频率明显增加(p=0.001,OR=4.03;p=0.016,OR=2.28),DRB1*0901的频率明显减低(p=0.023,OR=0.43)。③与健康对照组比较,白细胞正常组等位基因DRB1*08032,DRB1*1501,DRB1*0901频率无统计学差异(P>0.05)。④与使用他巴唑白细胞正常组比较,他巴唑致白细胞减少组ANCA阳性率明显增加(x2=4.878,p=0.027);与服用丙硫氧嘧啶白细胞正常组比较,服用丙硫氧嘧啶白细胞减少组ANCA阳性率增加,但无统计学差异(p=0.404);无论在白细胞减少组还是在白细胞正常组,与服用他巴唑患者比较,服用丙硫氧嘧啶患者ANCA阳性率均增加,但无统计学差异(x~2=0.287,p=0.592;x~2=0.141,p=0.707)。⑤无论在白细胞减少组还是在白细胞正常组,与未携带等位基因DRB1*08032和DRB1*1501患者比较,携带者血清中ANCA阳性率明显增加(P<0.05);与未携带等位基因DRB1*0910患者比较,携带者血清中ANCA阳性率减低,但无统计学差异(p>0.05)。⑥白细胞减少组甲状腺功能与白细胞正常组比较,FT3、FT4、TSH水平无统计学差异(p>0.05);白细胞减少组甲状腺相关抗体与白细胞正常组比较,TRAb、TGAb、TMAb阳性率均无统计学差异(p>0.05)。
结论①HLA-DRB1 *08032、HLA-DRB1*1501等位基因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等位基因可能ATD致白细胞减少的保护基因或抗性基因。②免疫反应可能参与了ATD致白细胞减少的发生。③血清ANCA阳性与是否携带某种DRB1等位基因可能有关,免疫反应可能存在遗传易感性。④ATD致白细胞减少的发生与甲状腺激素水平及甲状腺相关抗体可能无关。
Objective To investigate the relationship between HLA-DRB1 alleles polymorphism, antineutropil cytoplasmic antibody (ANCA) and susceptibility to Antithyroid drug-ind- uced leucocytopenia in patients with Graves disease (GD) in Anhui Han Chinese.
Methods①The HLA-DRB1*08032, DRB1*1501 and DRB1*0901 allele frequencies were determined by the polymerase chain reaction based sequence-specific primer (PC- R-SSP) method in 76 patients with Graves disease who had Antithyroid drug(ATD) induced leucocytopenia and 98 patients with Graves disease treated with ATD, who were free from leucocytopenia and 230 healthy Controls.②Indirect immu- nofluorescence assay (IIF) was used to detect ANCA;Positive, then further EUROA- SSAY were used to detect anti-Myeloperoxidase(MPO) antibody and anti-Proteinase- 3(PR3) antibody in sera from 76 patients with Graves disease who had Antithyroid drug(ATD) -induced leucocytopenia and 98 patients with Graves disease treated with ATD, who were free from leucocytopenia.
Result①compared with controls,The allele frequencies of DRB1*08032 and DRB1*1501 were obviously increased(p=0.00,OR=3.06;p=0.042,OR=1.77),while that of HLA-DRB1*0901 were significantly decreased (p=0.01,OR=0.33)in Antithyroid drug-induced leucocytopenia patients.②compared with GD patients without leucocynt- openia, The allele frequencies of DRB1*08032 and DRB1*1501 were obviously increased(p=0.001,OR=4.03;p=0.016,,OR=2.28),while that of HLA-DRB1 *0901 were significantly decreased (p=0.023,OR=0.43) in Antithyroid drug-induced leucocytopenia patients.③compared with controls,the allele frequencies of HLA-DRB1*0803- 2,DRB1*1501 and DRB1*0901 had no statistically significant diff- erence in GD patients without leucocytopenia (p>0.05).④compared with GD patients treated with MMI who were free from leucocytopenia, the ANCA frequencies were obviously increased in GD patients who had MMI-induced leucocytopenia (x~2=4.878,p=0.027) ; compared with GD patients treated with PTU who were free from leucocytopenia, the ANCA frequencies were increased in GD patients who had PTU-induced leucocytopenia,but the difference was not statistically significant (p=0.404); Whether in GD patients with leucocytopenia or in GD patients without leucocytopenia,compared with GD patients treated with MMI , the ANCA frequencies were increased in GD patients treated with PTU, but the difference was not statistically significant (x~2=0.287,p=0.592;x~2=0.141,p=0.707).⑤Whether in GD patients with leucocytopenia or in GD patients without leucocytopenia,compared with GD patients who is not carrying DRB1 *08032, DRB1*1501,DRB1*0901 allele, the ANCA frequencies were significantly increased in GD patients who is carrying it(p<0.05); compared with GD patients who is carrying DRB1 *0901allele, the ANCA frequencies were decreased in GD patients who is carrying it,but the difference was not statistically significant (p>0.05).⑥The difference in thyroxine between GD patients with leuc- ocytopenia and GD patients without leucocytopenia was not statistically significant (p>0.05); The difference in the thyroid-ralated antibodies between GD patients with leucocytopenia and GD patients without leucocytopenia was not statistically significant(p>0.05).
Conclusion①The DRB1*08032,HLA-DRB1*1501 alleles may be susceptible genes to Antithyroid drug -induced leucocytopenia in Anhui; while HLA-DRB1*0901 alleles may be protective genes or resistant genes.②Immune response may be involved in its development.③ANCA may be associated with whether the patient carrys a certain allele.The occurrence of immune response is based on the genetic susceptibili- ty.④There may be no correlation between Antithyroid drug -induced leucocytopenia and the elevation in thyoxine and the positive thyroid-related antibodies in GD patients.
方法①采用聚合酶链反应-序列特异性引物(PCR-SSP)方法检测76例使用ATD致白细胞减少的患者、98例使用ATD白细胞正常患者和230名健康对照组的HLA-DRB1*08032,DRB1*1501,DRB1*0901的等位基因频率。②采用间接免疫荧光法( IIF)检测76例ATD致白细胞减少的患者、98例使用ATD白细胞正常患者血清中的ANCA。阳性者则进一步用应用斑点法测定抗髓过氧化物酶(MPO)抗体及抗蛋白酶3(PR3)抗体。
结果①与健康对照组比较,白细胞减少组DRB1*08032,DRB1*1501频率明显增加(p=0.00,OR=3.06;p=0.042,OR=1.77),DRB1*0901的频率明显减低(p=0.01,OR=0.33)。②与白细胞正常组比较,白细胞减少组DRB1*08032和DRB1*1501频率明显增加(p=0.001,OR=4.03;p=0.016,OR=2.28),DRB1*0901的频率明显减低(p=0.023,OR=0.43)。③与健康对照组比较,白细胞正常组等位基因DRB1*08032,DRB1*1501,DRB1*0901频率无统计学差异(P>0.05)。④与使用他巴唑白细胞正常组比较,他巴唑致白细胞减少组ANCA阳性率明显增加(x2=4.878,p=0.027);与服用丙硫氧嘧啶白细胞正常组比较,服用丙硫氧嘧啶白细胞减少组ANCA阳性率增加,但无统计学差异(p=0.404);无论在白细胞减少组还是在白细胞正常组,与服用他巴唑患者比较,服用丙硫氧嘧啶患者ANCA阳性率均增加,但无统计学差异(x~2=0.287,p=0.592;x~2=0.141,p=0.707)。⑤无论在白细胞减少组还是在白细胞正常组,与未携带等位基因DRB1*08032和DRB1*1501患者比较,携带者血清中ANCA阳性率明显增加(P<0.05);与未携带等位基因DRB1*0910患者比较,携带者血清中ANCA阳性率减低,但无统计学差异(p>0.05)。⑥白细胞减少组甲状腺功能与白细胞正常组比较,FT3、FT4、TSH水平无统计学差异(p>0.05);白细胞减少组甲状腺相关抗体与白细胞正常组比较,TRAb、TGAb、TMAb阳性率均无统计学差异(p>0.05)。
结论①HLA-DRB1 *08032、HLA-DRB1*1501等位基因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等位基因可能ATD致白细胞减少的保护基因或抗性基因。②免疫反应可能参与了ATD致白细胞减少的发生。③血清ANCA阳性与是否携带某种DRB1等位基因可能有关,免疫反应可能存在遗传易感性。④ATD致白细胞减少的发生与甲状腺激素水平及甲状腺相关抗体可能无关。
Objective To investigate the relationship between HLA-DRB1 alleles polymorphism, antineutropil cytoplasmic antibody (ANCA) and susceptibility to Antithyroid drug-ind- uced leucocytopenia in patients with Graves disease (GD) in Anhui Han Chinese.
Methods①The HLA-DRB1*08032, DRB1*1501 and DRB1*0901 allele frequencies were determined by the polymerase chain reaction based sequence-specific primer (PC- R-SSP) method in 76 patients with Graves disease who had Antithyroid drug(ATD) induced leucocytopenia and 98 patients with Graves disease treated with ATD, who were free from leucocytopenia and 230 healthy Controls.②Indirect immu- nofluorescence assay (IIF) was used to detect ANCA;Positive, then further EUROA- SSAY were used to detect anti-Myeloperoxidase(MPO) antibody and anti-Proteinase- 3(PR3) antibody in sera from 76 patients with Graves disease who had Antithyroid drug(ATD) -induced leucocytopenia and 98 patients with Graves disease treated with ATD, who were free from leucocytopenia.
Result①compared with controls,The allele frequencies of DRB1*08032 and DRB1*1501 were obviously increased(p=0.00,OR=3.06;p=0.042,OR=1.77),while that of HLA-DRB1*0901 were significantly decreased (p=0.01,OR=0.33)in Antithyroid drug-induced leucocytopenia patients.②compared with GD patients without leucocynt- openia, The allele frequencies of DRB1*08032 and DRB1*1501 were obviously increased(p=0.001,OR=4.03;p=0.016,,OR=2.28),while that of HLA-DRB1 *0901 were significantly decreased (p=0.023,OR=0.43) in Antithyroid drug-induced leucocytopenia patients.③compared with controls,the allele frequencies of HLA-DRB1*0803- 2,DRB1*1501 and DRB1*0901 had no statistically significant diff- erence in GD patients without leucocytopenia (p>0.05).④compared with GD patients treated with MMI who were free from leucocytopenia, the ANCA frequencies were obviously increased in GD patients who had MMI-induced leucocytopenia (x~2=4.878,p=0.027) ; compared with GD patients treated with PTU who were free from leucocytopenia, the ANCA frequencies were increased in GD patients who had PTU-induced leucocytopenia,but the difference was not statistically significant (p=0.404); Whether in GD patients with leucocytopenia or in GD patients without leucocytopenia,compared with GD patients treated with MMI , the ANCA frequencies were increased in GD patients treated with PTU, but the difference was not statistically significant (x~2=0.287,p=0.592;x~2=0.141,p=0.707).⑤Whether in GD patients with leucocytopenia or in GD patients without leucocytopenia,compared with GD patients who is not carrying DRB1 *08032, DRB1*1501,DRB1*0901 allele, the ANCA frequencies were significantly increased in GD patients who is carrying it(p<0.05); compared with GD patients who is carrying DRB1 *0901allele, the ANCA frequencies were decreased in GD patients who is carrying it,but the difference was not statistically significant (p>0.05).⑥The difference in thyroxine between GD patients with leuc- ocytopenia and GD patients without leucocytopenia was not statistically significant (p>0.05); The difference in the thyroid-ralated antibodies between GD patients with leucocytopenia and GD patients without leucocytopenia was not statistically significant(p>0.05).
Conclusion①The DRB1*08032,HLA-DRB1*1501 alleles may be susceptible genes to Antithyroid drug -induced leucocytopenia in Anhui; while HLA-DRB1*0901 alleles may be protective genes or resistant genes.②Immune response may be involved in its development.③ANCA may be associated with whether the patient carrys a certain allele.The occurrence of immune response is based on the genetic susceptibili- ty.④There may be no correlation between Antithyroid drug -induced leucocytopenia and the elevation in thyoxine and the positive thyroid-related antibodies in GD patients.
引文
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14.Guma M, Salinas I, Recerter J.L, et al.Frequency of antineutroPhil Cytoplasmic antibody in Graves’disease patients treated with methimazole.J Clin Endocrinol Metab. 2003,88(5):2141-2146
15.徐旭东,赵明辉,章友康等.丙基硫氧嘧啶导致的抗中性粒细胞胞质抗体阳性小血管炎及其靶抗原研究.中华内科杂志2002,641(6):404-407
16.Harper L,Cockwell P,Savage CO. Case of propylthiouracil-induced ANCA asso- ciated small vessel vasculitis. Nephrol Dial Transplant.1998,13 : 455-458.
17.Kitahara T,Hiromura K,Maezawa A,etal.Case of propylthiouracil-induced vasculitis associated with anti-neutrophil cytoplasmic antibody(ANCA) ; review of literature. Clin Nephrol .1997,47 :336-340.
18.范丽安,周光炎.人类基因组MHC测序及其免疫学意义[J].上海免疫学杂志.1999,19(6):321-327
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11. Afeltra A,Paggi A,De Rosa F.G,et al.Antineutrophil cytoplasmic Antibodies in autoimmune thyroid disorders.Endocr Res.1998,24(2):185-194
12.Sera N,Ashizawa K,Ando T,et al.Treatment with propylthiourcil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves’disease.Thyroid.2000,10(7):59
13.Akamizu T,Ozaki S,Hiratani H, et al.Drug-induced neutropenia Associated with anti-neutrophil cytoplasmic antibodies(ANCA):Possible involvement of complem- ent in granulocyte cytotoxicity.Clin Exp Immunol.2002,127(1):92-98
14.Guma M, Salinas I, Recerter J.L, et al.Frequency of antineutroPhil Cytoplasmic antibody in Graves’disease patients treated with methimazole.J Clin Endocrinol Metab. 2003,88(5):2141-2146
15.徐旭东,赵明辉,章友康等.丙基硫氧嘧啶导致的抗中性粒细胞胞质抗体阳性小血管炎及其靶抗原研究.中华内科杂志2002,641(6):404-407
16.Harper L,Cockwell P,Savage CO. Case of propylthiouracil-induced ANCA asso- ciated small vessel vasculitis. Nephrol Dial Transplant.1998,13 : 455-458.
17.Kitahara T,Hiromura K,Maezawa A,etal.Case of propylthiouracil-induced vasculitis associated with anti-neutrophil cytoplasmic antibody(ANCA) ; review of literature. Clin Nephrol .1997,47 :336-340.
18.范丽安,周光炎.人类基因组MHC测序及其免疫学意义[J].上海免疫学杂志.1999,19(6):321-327
19.谷奕,李梅,邱明才.Graves病甲亢白细胞减少与HLA-DQA1基因多态性的关联性.Tianjin Med J.Jan 2006,34(1):10-12.
20.Murakami Y,Sasak I. Serum concentrations of granulocyte colony-stimulating factor (G-CSF) in antithyroid drug-induced agranulocytosis[J].Endocr J,2004,51 (6):579-585.
21.Fukata S,Kuma k,Sugawara M, etal.Granulocyte colony-stimulating factor(G-CSF) does not improve recovery from antithyriod drug-induced agranulocytosis:aprosp-ective study[J].Thyroid.1999,9:29-31.
22.栾晓军,肖平,胡利东.粒细胞集落刺激因子受体在甲亢药物治疗患者中的表达及其临床意义.华中科技大学学报(医学版).2006,35(4):476
23.Avalos BR. Molecular analysis of the granulocyte colony-stimulating factor recep- tor.[J].Blood ,1996,88(3):761-777.