Graham Jinko, Hagopian William A, Kockum Ingrid, Li Lou Sheng, Sanjeevi Carani B, Lowe Robert M, Schaefer Jonathan B, Zarghami Marjan, Day Heather L, Landin-Olsson Mona, Palmer Jerry P, Janer-Villanueva Marta, Hood Leroy, Sundkvist Göran, Lernmark Ake, Breslow Norman, Dahlquist Gisela, Blohmé Göran
Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, Canada.
Diabetes. 2002 May;51(5):1346-55. doi: 10.2337/diabetes.51.5.1346.
Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.
通过逻辑回归分析，在971例0至34岁的1型糖尿病初发患者和702例对照受试者中，确定了1型糖尿病风险基因HLA、胰岛素可变数目串联重复序列（INS VNTR）和细胞毒性T淋巴细胞相关抗原4（CTLA-4）与抗谷氨酸脱羧酶65抗体（GADAs）、胰岛细胞抗原512/胰岛抗原2（ICA512/IA-2）、胰岛素和胰岛细胞自身抗体之间的年龄依赖性关联。GADAs在年轻患者中与HLA-DQ2相关，但在老年患者中不相关（P = 0.009）。胰岛素自身抗体与年龄呈负相关（P < 0.0001），但与DQ8呈正相关（P = 0.03），与INS VNTR呈正相关（P = 0.04），支持可能的免疫耐受诱导。ICA512/IA-2与年龄呈负相关（P < 0.0001），与DQ2呈负相关（P < 0.0001），但与DQ8呈正相关（P = 0.04）。男性比女性更有可能GADA、胰岛细胞自身抗体及所有四种自身抗体标志物呈阴性（P = 0.004）。CTLA-4 3'端微卫星标记与任何一种自身抗体均无关联。我们得出结论，在评估1型糖尿病发生风险时，年龄和HLA-DQ及INS VNTR等遗传因素需要与胰岛自身抗体标志物相结合。
