Schlosser Michael, Wassmuth Ralf, Strebelow Martina, Rjasanowski Ilona, Ziegler Manfred
Institute of Pathophysiology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany.
Ann N Y Acad Sci. 2003 Nov;1005:98-108. doi: 10.1196/annals.1288.011.
The study aimed to compare the HLA specificities of AAb-positive healthy schoolchildren with those of patients with type 1 diabetes (T1D). HLA-DRB1 and DQB1 alleles were determined in 178 AAb-positive and 339 AAb-negative schoolchildren aged 6-17 years without first-degree relatives with T1D and in 274 patients with T1D. AAbs against glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA-2A), and insulin (IAA) were determined by (125)I-antigen binding, and islet cell cytoplasmic antibodies (ICAs) immunohistochemically. Here, 82.6% (147/178) of AAb-positive schoolchildren had single AAbs and 17.4% (31/178) had multiple AAbs. In both groups, GADA occurred with highest and IAA with lowest frequency. In children with single AAbs at levels between the 99th and 99.9th percentile, frequencies of the diabetes-associated DRB1 (03, 04) and DQB1 (02, 0302) alleles and the protective DRB1 (15) and DQB1 (0602) alleles did not differ from those of controls. In patients, the positive associations were confirmed for DRB104 (OR = 5.39) and DQB10302 (OR = 9.05), whereas DRB115 (OR = 0.05) and DQB10602 (OR = 0.06) were negative-associated (p < 0.001). The same association was found in schoolchildren with multiple AAbs for DRB104 (OR = 3.84), DQB10302 (OR = 4.95), and DRB115 (OR = 0.1; p < 0.001-0.014), and with high-titer single AAbs (>/=99.9th percentile), but none of them had DQB10602. The highest risk genotype DQB1*02/*0302 occurred in 36.5% of patients (OR = 21.07) and in 19.3% of children with multiple AAbs (OR = 8.8; p<0.001). It is concluded that probands with multiple and high-titer single AAbs in the general population have the same genetic predisposition for T1D as patients and are therefore at highest risk for the disease.
该研究旨在比较自身抗体阳性的健康学童与1型糖尿病（T1D）患者的HLA特异性。对178名自身抗体阳性和339名自身抗体阴性、年龄在6至17岁且无T1D一级亲属的学童以及274名T1D患者进行了HLA - DRB1和DQB1等位基因检测。通过¹²⁵I抗原结合法检测了抗谷氨酸脱羧酶（GADA）、蛋白酪氨酸磷酸酶（IA - 2A）和胰岛素（IAA）的自身抗体，并通过免疫组织化学方法检测了胰岛细胞胞浆抗体（ICA）。在此，82.6%（147/178）的自身抗体阳性学童有单一自身抗体，17.4%（31/178）有多重重自身抗体。在两组中，GADA出现频率最高，IAA出现频率最低。在自身抗体水平处于第99百分位和第99.9百分位之间的单一自身抗体儿童中，糖尿病相关的DRB1（03，04）和DQB1（02，0302）等位基因以及保护性DRB1（15）和DQB1（0602）等位基因的频率与对照组无差异。在患者中，DRB104（比值比 = 5.39）和DQB10302（比值比 = 9.05）的阳性关联得到证实，而DRB115（比值比 = 0.05）和DQB10602（比值比 = 0.06）呈负相关（p < 0.001）。在有多重重自身抗体的学童中，DRB104（比值比 = 3.84）、DQB10302（比值比 = 4.95）和DRB115（比值比 = 0.1；p < 0.001 - 0.014）也发现了相同的关联，在高滴度单一自身抗体（≥第99.9百分位）的学童中也是如此，但他们均无DQB10602。最高风险基因型DQB1*02/*0302在36.5%的患者中出现（比值比 = 21.07），在19.3%有多重重自身抗体的儿童中出现（比值比 = 8.8；p<0.001）。结论是，一般人群中具有多重重和高滴度单一自身抗体的先证者与患者具有相同的T1D遗传易感性，因此患该疾病的风险最高。
