我国汉族1型糖尿病HLA基因与4种胰岛自身抗体关系的研究

摘要

Objective To explore the relationship of human leukocyte antigen (HLA)-DRB1 and DQB1 genotypes with the four islet autoantibodies, including glutamic acid decarboxyase antibody (GADA), zinc transporters antibody (ZnT8A), protein tyrosine phosphatase-2 antibody (IA-2A), and insulin autoantibody (IAA), in the Chinese Han people with T1DM. Methods A cross-sectional and case-control study was carried out The HLA gene polymorphism of HLA-DRB1 and DQB1 were examined with PCR-SSO method, the GADA, ZnTSA, IA-2A, and IAA were detected by radiornimmunity ligand assay. Results (1) The frequencies of DRB1 * 0301-DQB1 * 0201, DRB1 * 0405-DQB1 * 0302, and DRB1 * 0901-DQB1 * 0303 haplotypes were significantly higher in T1DM patients than in the controls (P<0. 01). (2) The GADA and ZnT8A positive rate in T1DM patients with DRB1 * 0901 genotype was significantly higher than those without it (P<0.05), and the IA-2A positive rate in T1DM patients with DRB1 * 0405 genotype was much higher (P<0. 05). (3) HLA-DRB1 * 0901 genotype and HLA-DRB1 * 0901-DQB1 * 0303 haplotype were independent risk factors for positive autoantibodies in rnT1DM patients (P<0. 05). (4) Lower C-peptide was found in those who were with higher BMI, HLA high risk haplotypes, and positive ZnT8A (P<0. 05). Conclusion The discordant association of autoantibodies with high risk HLA gene may indicate the different immunology mechanism of those autoantibodies. BMI, HLA high risk haplotypes, and ZnT8A positive rate may affect the p-cell function in the process of diabetes mellitus in T1DM patients.%目的 探讨T1DM患者HLA-DRB1,DQB1基因型与谷氨酸脱羧酶抗体(GADAb)、锌转运体8自身抗体(ZnT8A)、蛋白酪氨酸磷酸酶抗体(IA-2A)和胰岛素自身抗体(IAA),以及胰岛功能等临床特征间的相互关系. 方法 进行横断面、病例对照研究,采用PCR-SSO技术进行HLA基因分型、放射免疫配体法检测胰岛自身抗体(GADAb、ZnT8A、IA-2A和IAA). 结果 (1)T1DM患者DRB1* 0301-DQB1* 0201、DRB1* 0405-DQB1* 0302、DRB1* 0901-DQB1* 0303单倍型频率增高(P＜0.01);(2)携带DRB1* 0901者ZnT8A和GADAb的阳性率均显著高于非携带该等位基因者(P＜0.05);携带DRB1* 0405者的IA-2A阳性率显著增高(P＜0.05); (3)HLA-DRB1* 0901基因型和HLA-DRB1* 0901-DQB1* 0303单倍型是T1DM患者自身抗体阳性的独立危险因素(P＜0.05);(4)高BMI、携带HLA易感单倍型及ZnT8A阳性者FC-P水平较低(P＜0.05). 结论 影响胰岛自身抗体阳性率的HLA高危基因各自不同,提示调节这些自身抗体产生的免疫机制存在着差异;BMI、HLA易感基因携带情况及ZnT8A阳性率可能影响T1DM患者随病程进展的胰岛功能衰竭速度.