组织相容性复合体-非经典基因与1型糖尿病临床状态相关性的研究

目的 研究组织相容性复合体-DMA、DMB基因与中国人1型糖尿病临床状态的相关性。方法 根据性别、发病年龄、起病急缓、起病时酮症发生情况、胰岛β细胞残存功能(就诊时空腹C-肽水平)等临床状态的不同,将1型糖尿病患儿进行分组,研究DM易感性基因和二聚体在不同临床状态分组中的频率分布情况。结果 (1)DMA*0103、DMB*0103基因在1型糖尿病患儿中的频率显著高于正常对照,分别为50．0％、4．0％,为1型糖尿病的易感性基因。DMA*0103／DMB*0103、DMA*0103／DMB*0104、DMA*0103／DMB*0101二聚体在1型糖尿病患儿中的频率也显著增高,分别为15％、24％、13％,为1型糖尿病的易感性二聚体。(2)携带DMB*0103基因或DM易感性二聚体的个体,在C—肽低水平患儿组中的频率均显著高于C-肽高水平组。DM易感性二聚体与患儿的发病年龄及发病时酮症发生情况也有显著的相关性,携带DM易感性二聚体的个体,10岁前发生糖尿病的概率显著增加,新发生1型糖尿病时也更易出现酮症或酮症酸中毒。结论 DM基因和二聚体均与1型糖尿病临床状态存在显著的相关性,1型糖尿病的临床状态异质性有一定的遗传机理起作用。

Association of human leukocyte antigen non-classical genes with type 1 diabetes

OBJECTIVE: HLA-DMA and DMB are non-classical genes whose product (DM molecules) plays an important role in antigen presentation. Our present study was designed to investigate the relationship between human leukocyte antigen-DMA, -DMB and clinical status heterogeneity of type 1 diabetes. METHODS: A total of 80 children (male 36, female 44) with type 1 diabetes were selected as research subjects. Diagnosis of type 1 diabetes was made according to WHO criteria. The range of age at onset of type 1 diabetes was 2.5 - 14 years. Ninety-one healthy adult blood donors were selected as normal controls. Polymerase chain reaction and dot blot hybridization techniques were used to classify DMA and DMB alleles. Patients with type 1 diabetes were classified into different groups according to different clinical status, including sex, age of onset, ketosis onset situation on diagnosis, remained function of islet beta cell, etc. Then distribution of DM susceptive alleles and heterodimer in different clinical groups were studied. RESULTS: The frequencies of DMA * 0103 and DMB * 0103 alleles in patients were significantly increased (50% vs. 8%, 43% vs. 22%, respectively), these two alleles confer susceptibility to type 1 diabetes in Chinese. The frequencies of DMA * 0103/DMB * 0102, DMA * 0103/DMB * 0103 and DMA * 0103/DMB * 0101 heterodimers were also increased in the patients. The above heterodimers confer predisposition to type 1 diabetes. Both DMB * 0103 allele and DM susceptive heterodimers are related to islet beta cell function on diagnosis. The patients with DMB * 0103 allele or DM susceptive heterodimers were significantly increased in the patients with lower C-peptide level on diagnosis (56% vs. 29%; 58% vs. 34% respectively). DM heterodimes were also related to onset age and ketosis-onset-situations of the patients. The patients carrying DM susceptive heterodimers had higher probability to suffer type 1 diabetes before 10 years of age and had the predisposition to ketosis or ketoacidosis on diagnosis. CONCLUSION: HLA- class II non-classical alleles-DMA and DMB may play an important role in pathogenesis of type 1 diabetes, and clinical status heterogeneity of type 1 diabetes may be related to genetic mechanism.