Max McGee National Research Center for Juvenile Diabetes, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Immunogenetics. 2010 Feb;62(2):101-7. doi: 10.1007/s00251-009-0417-4. Epub 2009 Dec 23.
The onset of type 1 diabetes can occur at any age, with as many as half of all cases diagnosed after age 15. Despite this wide distribution in age at diagnosis, most genetic studies focus on cases diagnosed in childhood or during early adulthood. To better understand the genetics of late-onset type 1 diabetes, we collected a Finnish case/control cohort with all cases diagnosed between ages 15 and 40. We genotyped 591 probands and 1,538 control subjects at regions well established as susceptibility loci in early onset type 1 diabetes. These loci were then tested for disease association and age-at-diagnosis effects. Using logistic regression, we found that single-nucleotide polymorphisms (SNPs) at the INS, PTPN22, and IFIH1 loci were associated with late-onset disease (OR (95%CI) = 0.57(0.47-0.69), p = 2.77 x 10(-9); OR (95%CI) = 1.50 (1.27-1.78), p = 3.98 x 10(-6); and OR (95%CI) = 0.81(0.71-0.93), p = 0.0028, respectively). In contrast, a disease association was not detected for two SNPs at the IL2RA locus (rs11594656 and rs41295061). Despite this, we did find an independent age-at-diagnosis effect for each IL2RA SNP using a multivariate Cox proportional hazards model (p = 0.003, 0.002, respectively). Taken together, polymorphisms at the IL2RA locus were a major determinant of age at diagnosis in our cohort with an effect at par with the HLA-DQ2/DQ8 genotype as measured by hazard ratios. These findings suggest that the IL2RA locus controls both the susceptibility to disease and its time of occurrence. Thus, we believe the IL2/IL2R axis represents a potential therapeutic target for delaying the onset of disease.
1 型糖尿病的发病年龄可在任何年龄，其中多达一半的病例在 15 岁以后确诊。尽管诊断时的年龄分布广泛，但大多数遗传研究都集中在儿童期或成年早期确诊的病例上。为了更好地了解迟发性 1 型糖尿病的遗传学，我们收集了一个芬兰病例对照队列，所有病例均在 15 至 40 岁之间确诊。我们对 591 名先证者和 1538 名对照在早期发病 1 型糖尿病中已确定为易感位点的区域进行了基因分型。然后对这些位点进行疾病关联和发病年龄效应检测。使用逻辑回归，我们发现 INS、PTPN22 和 IFIH1 基因座的单核苷酸多态性（SNP）与迟发性疾病相关（OR（95%CI）=0.57（0.47-0.69），p=2.77x10(-9)；OR（95%CI）=1.50（1.27-1.78），p=3.98x10(-6)；OR（95%CI）=0.81（0.71-0.93），p=0.0028）。相比之下，IL2RA 基因座的两个 SNP（rs11594656 和 rs41295061）未检测到疾病相关性。尽管如此，我们确实使用多变量 Cox 比例风险模型发现了每个 IL2RA SNP 的独立发病年龄效应（p=0.003，0.002）。总的来说，IL2RA 基因座的多态性是我们队列中发病年龄的主要决定因素，其效应与 HLA-DQ2/DQ8 基因型相当，风险比测量。这些发现表明，IL2RA 基因座既控制疾病的易感性，又控制疾病的发生时间。因此，我们认为 IL2/IL2R 轴代表了延迟疾病发作的潜在治疗靶点。
