Caillat-Zucman S, Garchon H J, Timsit J, Assan R, Boitard C, Djilali-Saiah I, Bougnères P, Bach J F
Institut National de la Sante et de la Recherche Medicale U 25, Hôpital Necker, Paris, France.
J Clin Invest. 1992 Dec;90(6):2242-50. doi: 10.1172/JCI116110.
The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB103, DRB104, DQB10201, DQB10302, DQA10301, and DQA10501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB103-DQB10201 and the DRB10402 or DRB10405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.
胰岛素依赖型糖尿病（IDDM）与某些HLA等位基因的关联在儿科患者中已有充分记录。虽然50%的病例在20岁以后发病，但成人发病的IDDM是否存在类似关联尚不清楚。采用基因扩增后的寡核苷酸分型方法，对402例I型糖尿病患者和405名健康对照者（均为白种人）进行了HLA II类DRB1、DQA1和DQB1等位基因研究。DRB103、DRB104、DQB10201、DQB10302、DQA10301和DQA10501等位基因在糖尿病患者中确实富集，并且在携带DRB103-DQB10201以及DRB10402或DRB10405-DQB1*0302单倍型的患者中观察到最高的相对风险。然而，这些等位基因或特定残基单独一个都不能解释IDDM的易感性。此外，根据发病年龄，HLA II类基因谱存在重大差异。15岁以后发病的患者（n = 290）非DR3/非DR4基因型的比例显著高于儿童期发病的患者（n = 112），而DR3/4基因型的比例较低。这些非DR3/非DR4患者虽然临床上表现为1型IDDM患者，但诊断时胰岛细胞抗体频率较低，初始胰岛素缺乏明显较轻。这些受试者可能代表了IDDM患者中的一个特殊亚组，其频率随年龄增加。数据证实了IDDM的遗传异质性，因此在将源自儿童IDDM的遗传概念外推至成年患者时需谨慎。
