Eerligh P, Koeleman B P C, Dudbridge F, Jan Bruining G, Roep B O, Giphart M J
Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Genes Immun. 2004 Jan;5(1):36-40. doi: 10.1038/sj.gene.6364036.
Genetic association with type 1 diabetes (T1D) has been established for two chromosomal regions: HLA DQ/DR (IDDM1) and INS VNTR (IDDM2). To identify additional genetic markers, we tested polymorphisms in regulatory regions of several cytokine and important metabolic genes. These polymorphisms exhibit functional consequences for expression and function. Functional genetic polymorphisms of proinflammatory (T-helper-1: IL-2, IL-12 and IFN-gamma), anti-inflammatory (T-helper-2: IL-4, IL-6 and IL-10) and metabolic (IGF-I, VDR and INS) genes were determined in 206 Dutch simplex families with juvenile onset T1D and the results were analysed using the transmission disequilibrium test. Significantly increased transmission to T1D probands was observed for the loci IDDM1, IDDM2 and the vitamin D receptor. Although none of the other individual polymorphisms was associated with disease individually, the combination of T-helper-2 and metabolic/growth alleles IL-10()R2, IL-4()C, VDR()C and IGF-I()wt was found to be transmitted more frequently than expected (67%, P(c)=0.015). We conclude that additional genetic predisposition to T1D is defined by combinations of markers (eg Th2 and metabolic) rather than by a single marker. The consequences of the increased transmission of a low Th2 expressing genotypes together with a normal Th1 profile may result in a net proinflammatory cytokine expression pattern.
1型糖尿病（T1D）与两个染色体区域存在遗传关联：HLA DQ/DR（IDDM1）和胰岛素基因可变数目串联重复序列（INS VNTR，IDDM2）。为了鉴定其他遗传标记，我们检测了多个细胞因子和重要代谢基因调控区域的多态性。这些多态性对基因表达和功能具有功能性影响。我们在206个荷兰青少年起病的T1D单基因家系中，测定了促炎（辅助性T细胞1型：IL-2、IL-12和IFN-γ）、抗炎（辅助性T细胞2型：IL-4、IL-6和IL-10）和代谢（胰岛素样生长因子I、维生素D受体和胰岛素）基因的功能性遗传多态性，并使用传递不平衡检验分析结果。观察到IDDM1、IDDM2和维生素D受体基因座向T1D先证者的传递显著增加。虽然其他单个多态性均未单独与疾病相关，但发现辅助性T细胞2型和代谢/生长等位基因IL-10（）R2、IL-4（）C、VDR（）C和IGF-I（）wt的组合传递频率高于预期（67%，P（c）=0.015）。我们得出结论，T1D的额外遗传易感性是由标记组合（如辅助性T细胞2型和代谢相关标记）定义的，而非单个标记。低辅助性T细胞2型表达基因型与正常辅助性T细胞1型谱的传递增加，其结果可能导致促炎细胞因子表达模式的净增加。
