Gene analysis of HLA class II antigens in relation to the development of IDDM in Japanese

胰岛素依赖型糖尿病（IDDM）的发生可能是由于自身免疫过程破坏胰腺β细胞的结果。它与某些HLA抗原有关，但与IDDM相关的HLA类型在不同民族之间存在差异。在白种人中，Asp在HLA DQ B57的存在可保护免于IDDM，但日本的许多IDDM患者在该位置具有Asp。为了明确日本人胰岛素依赖型糖尿病易感性HLA抗原，我们用聚合酶链反应和序列特异性寡核苷酸杂交技术分析了日本人胰岛素依赖型糖尿病患者的DRB 1、DQA 1和DQB 1基因。结果发现：（1）DR 4、DR 9与IDDM呈正相关，DR 2、DRw 11与IDDM呈负相关;（2）DR 4-Dw 15（DRB 1 *0405）、DR 9、DQA 1 *0301、DQB 1 *0401等位基因与IDDM呈正相关。单倍型DRB 1 *0405-DQA 1 *0301-DQB 1 *0401（RR=4.4）、DRw 8-DQA 1 *0301-DQB 1 *0302（RR=9.7）和DR 9-DQA 1 *0301-DQB 1 *0303（RR=2.2）与IDDM呈正相关。（3）在3个家系中，父母一方为IDDM，另一方为IDDM，最易患的基因型为[DRB 1 *0405-DQA 1 *0301-DQB 1 *0401] / [DRw 8-DQA 1 *0301-DQB 1 *0302]（RR=18.2）。DRB 1 *0405-DQA 1 *0301-DQB 1 *0401在2个父-子对中共享，DR 2-DQA 1 *0103-DQB 1 *0601在一个对中共享。在4对IDDM同胞中，3对具有2种单倍型，2对具有DRB 1 *0405-DQA 1 *0301-DQB 1 *0401（纯合子），1对具有[DRB 1 *0403-DQA 1 *0301-DQB 1 *0302] / [DRB 1 *0405-DQA 1 *0301-DQB 1 *0401]。（4）临床特征和HLA亚型的比较显示，DR 9、DQA 1 * 0301和DQB 1 * 0303在CPR阴性患者中更常见，DR 1 *0405、DR w 8和DQA 1 *0401在CPR阳性患者中更常见。甲状腺自身抗体阳性患者DR 9、DQB 1 *0303频率较高，DRB 1 *0405、DRw 13和DQA 1 *0102频率较低。这些数据表明，DRB 1，DQA 1和DQB 1基因赋予IDDM易感性在日本和修改临床特征。

Insulin-dependent diabetes mellitus (IDDM) occurs as a result of destruction of pancreatic beta cells presumably by autoimmune process. It is related to certain HLA antigens, but the HLA types which correlate with IDDM vary among different ethnic groups. In Caucasians, the presence of Asp at HLA DQ B57 protects from IDDM, but many IDDM patients in Japan have Asp at this position. In order to clarify the IDDM susceptibility HLA antigens in Japanese, we analyzed DRB1, DQA1 and DQB1 genes of IDDM patients by polymerase chain reaction and sequence-specific oligonucleotide hybridization. We found that, (1) DR4 and DR9 were positively cor-related while DR2 and DRw11 negatively correlated with IDDM; (2) DR4-Dw15(DRB1*0405), DR9, DQA1*0301, DQB1*0401 alleles were positively correlated with IDDM. As haplotypes, DRB1*0405-DQA1*0301-DQB1*0401(RR=4.4), DRw8-DQA1*0301-DQB1*0302(RR=9.7), and DR9-DQA1*0301-DQB1*0303(RR=2.2) were positively correlated with IDDM. The most susceptible genotype was [DRB1*0405-DQA1*0301-DQB1*0401] / [DRw8-DQA1*0301-DQB1*0302] (RR=18.2); (3) Among 3 families in which a parent and achild had IDDM. DRB1*0405-DQA1*0301-DQB1*0401 was shared in 2 parent-child pairs and DR2-DQA1*0103-DQB1*0601 was shared in one pair. Among 4 IDDM sib pairs, 3 shared two haplotypes, two sharing DRB1*0405-DQA1*0301-DQB1*0401 (homozygotic), and one sharing [DRB1*0403-DQA1*0301-DQB1*0302] / [DRB1*0405-DQA1*0301-DQB1*0401]. One IDDM sib pair shared only one haplotype, DRB1*0405-DQA1*0301-DQB1*0302; (4) Comparison of clinical features and HLA subtypes revealed that DR9, DQA1*0301 and DQB1*0303 were more frequent in CPR-negative patients, and DRB1*0405, DRw8, and DQA1*0401 were more frequent in CPR-positive patients. Patients with thyorid autoantibodies had DR9, DQB1*0303 more often and DRB1*0405, DRw13 and DQA1*0102 less frequently. These data indicate that DRB1, DQA1 and DQB1 genes confer IDDM susceptibility in Japanese and modify clinical features.