van der Auwera B, Schuit F, Lyaruu I, Falorni A, Svanholm S, Vandewalle C L, Gorus F K
Department of Biochemistry, Vrije Universiteit Brussel, Belgium.
J Clin Endocrinol Metab. 1995 Sep;80(9):2567-73. doi: 10.1210/jcem.80.9.7673396.
Whether genetic susceptibility for insulin-dependent diabetes mellitus (IDDM) at the 5' insulin gene polymorphic region (5' INS) interacts with human leukocyte antigen (HLA)-DQ-linked disease risk and whether it is associated with autoantibody formation is presently controversial. Diabetes registries allow more systematic reassessment of these questions. Two hundred and ninety-six Caucasian IDDM patients were recruited by the Belgian Diabetes Registry and sampled at disease onset, together with 195 ethnically matched control subjects. 5'INS genotypes were determined by Southern blotting, HLA-DQ by allele-specific oligotyping, and autoantibodies by validated immunoassays. The 5' INS 1/1 genotype was more prevalent in patients than in controls [relative risk (RR) = 2.3; P < 10(-4)]. Regardless of age at onset, the 5' INS 1/1 genotype occurred less frequently in patients with the high-risk genotype DQA10301-DQB10302/DQA10501-DQB10201 than in patients without it (P < 0.04). The RR associated with this high-risk HLA-DQ genotype (24.9; P < 10(-6)) was not affected by the presence or absence of the 5' INS 1/1 genotype. Combined positivity for the 5' INS 1/1 genotype and for one of three other HLA-DQ genotypes associated with an intermediate risk for IDDM conferred an age-independent RR of 12.1 (P < 10(-4)). In the absence of the 5' INS 1/1 genotype, intermediate-risk HLA-DQ genotypes no longer conferred a significant risk (2.9; not significantly different from 1). In subjects carrying neutral, protective, or infrequent HLA-DQ genotypes, the overall RR for IDDM was significantly lower than 1 (0.2; P < 10(-6)) in the absence of the 5' INS 1/1 genotype but not in its presence (0.8; not significantly different from 1). The 5' INS 1/1 genotype was not preferentially associated with immune markers for IDDM. In conclusion, regardless of age at onset and the presence of autoantibodies, 5' INS polymorphisms contribute preferentially to IDDM susceptibility in subjects without the highest HLA-DQ-associated risk.
胰岛素依赖型糖尿病（IDDM）在5'胰岛素基因多态性区域（5' INS）的遗传易感性是否与人类白细胞抗原（HLA）-DQ相关的疾病风险相互作用，以及它是否与自身抗体形成相关，目前存在争议。糖尿病登记处允许对这些问题进行更系统的重新评估。比利时糖尿病登记处招募了296名白种人IDDM患者，并在疾病发作时进行采样，同时选取了195名种族匹配的对照受试者。通过Southern印迹法确定5'INS基因型，通过等位基因特异性寡核苷酸分型确定HLA-DQ基因型，通过经过验证的免疫测定法确定自身抗体。5' INS 1/1基因型在患者中比在对照中更常见[相对风险（RR）= 2.3；P < 10(-4)]。无论发病年龄如何，携带高风险基因型DQA10301-DQB10302/DQA10501-DQB10201的患者中5' INS 1/1基因型的出现频率低于未携带该基因型的患者（P < 0.04）。与这种高风险HLA-DQ基因型相关的RR（24.9；P < 10(-6)）不受5' INS 1/1基因型存在与否的影响。5' INS 1/1基因型与其他三种与IDDM中度风险相关的HLA-DQ基因型之一的联合阳性赋予了与年龄无关的RR为12.1（P < 10(-4)）。在没有5' INS 1/1基因型的情况下，中度风险的HLA-DQ基因型不再赋予显著风险（2.9；与1无显著差异）。在携带中性、保护性或罕见HLA-DQ基因型的受试者中，在没有5' INS 1/1基因型时IDDM的总体RR显著低于1（0.2；P < 10(-6)），但在有该基因型时则不然（0.8；与1无显著差异）。5' INS 1/1基因型与IDDM的免疫标志物没有优先关联。总之，无论发病年龄和自身抗体的存在情况如何，5' INS多态性在没有最高HLA-DQ相关风险的受试者中对IDDM易感性的贡献更大。
