Sanjeevi C B, Höök P, Landin-Olsson M, Kockum I, Dahlquist G, Lybrand T P, Lernmark A
Karolinska Institute, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Tissue Antigens. 1996 Apr;47(4):275-83. doi: 10.1111/j.1399-0039.1996.tb02554.x.
The aim of this study was to determine the association between childhood insulin-dependent diabetes mellitus (IDDM) and HLA-DR4 subtypes and to test in a population-based investigation whether the DR4 association has an effect independent to that of DQ. First, HLA genotyping identified DR4 in 337/425 (79%) patients and 148/367 (40%) controls (Odds Ratio 5.67; p < 0.01). Second, a total of 14 DR4 subtypes were detected by PCR and sequence specific oligo probes. Only two DR4 subtypes, DRB10401 (62% patients and 25% controls; OR 4.95, p < 0.01) and 0404 (16% patients and 10% controls; OR 1.67, p < 0.05) were however positively associated with the disease. These two subtypes were positively associated only when linked to DQB10302-DQA10301 (DQ8) (56% patients and 14% controls; OR 7.69, p < 0.01; 15% patients and 10% controls; OR 1.55, p < 0.05, respectively). When DRB10401 was linked to DQB10301-DQA10301 (DQ7) (6% patients and 11% controls; OR 0.52, p < 0.05), this DR4 subtypes was negatively associated with IDDM. Third, tests of strongest association allowed the following ranking of alleles or haplotypes DQB1*0302-DQA1*0301 (DQ8) > DQB10302 > DRB10401 > DRB10404 and the association of DRB1*0401 has a significant effect in DQ8 positive IDDM patients. We conclude that the DR4 association with IDDM is secondary to DQ by linkage disequilibrium, which support the role of HLA-DQ as a primary genetic risk factor for IDDM.
本研究的目的是确定儿童胰岛素依赖型糖尿病（IDDM）与HLA - DR4亚型之间的关联，并在一项基于人群的调查中检验DR4关联是否具有独立于DQ的效应。首先，HLA基因分型在337/425（79%）的患者和148/367（40%）的对照中鉴定出DR4（优势比5.67；p < 0.01）。其次，通过聚合酶链反应（PCR）和序列特异性寡核苷酸探针共检测到14种DR4亚型。然而，只有两种DR4亚型，即DRB10401（62%的患者和25%的对照；OR 4.95，p < 0.01）和0404（16%的患者和10%的对照；OR 1.67，p < 0.05）与该疾病呈正相关。这两种亚型仅在与DQB10302 - DQA10301（DQ8）连锁时呈正相关（56%的患者和14%的对照；OR 7.69，p < 0.01；15%的患者和10%的对照；OR 1.55，p < 0.05）。当DRB10401与DQB10301 - DQA10301（DQ7）连锁时（6%的患者和11%的对照；OR 0.52，p < 0.05），这种DR4亚型与IDDM呈负相关。第三，最强关联测试得出以下等位基因或单倍型的排序：DQB1*0302 - DQA1*0301（DQ8）> DQB10302 > DRB10401 > DRB10404，并且DRB1*0401的关联在DQ8阳性的IDDM患者中有显著效应。我们得出结论，DR4与IDDM的关联是由于连锁不平衡而继发于DQ的，这支持了HLA - DQ作为IDDM主要遗传危险因素的作用。
