DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life,Diabetologia

当前位置： X-MOL 学术 › Diabetol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

DR15-DQ6 remains dominantly protective against type 1 diabetes throughout the first five decades of life
Diabetologia ( IF 8.4 ) Pub Date : 2021-07-16 , DOI: 10.1007/s00125-021-05513-4
Nicholas J Thomas _{1,

2} , John M Dennis ₁ , Seth A Sharp ₁ , Akaal Kaur ₃ , Shivani Misra ₃ , Helen C Walkey ₃ , Desmond G Johnston ₃ , Nick S Oliver ₃ , William A Hagopian ₄ , Michael N Weedon ₁ , Kashyap A Patel _{1,

2} , Richard A Oram _{1,

5}

Affiliation

Aims/hypothesis

Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased.

Methods

In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years.

Results

DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5–18 years OR 0.16 (95% CI 0.08, 0.31); age 19–30 years OR 0.10 (0.04, 0.23); and age 31–50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes.

Conclusions/interpretation

HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life.

Graphical abstract

中文翻译：

DR15-DQ6 在生命的前 50 年仍然对 1 型糖尿病具有显着的保护作用

目标/假设

在患有 1 型糖尿病的欧洲白人儿童中，原本常见的 HLA 单倍型 DR15-DQ6 很罕见，但具有高度保护性。目前已知成人发病的 1 型糖尿病比儿童发病的总体病例更多，但尚不清楚 DR15-DQ6 对老年发病的 1 型糖尿病是否具有保护作用。随着发病年龄的增加，我们试图量化 DR15-DQ6 对 1 型糖尿病的保护作用。

方法

在两个独立队列中，我们与人群对照相比，评估了 DR15-DQ6 治疗后 50 年内出现 1 型糖尿病病例的比例。在糖尿病后诊断研究支持系统 2 (ADDRESS-2) 队列 ( n = 1458) 中，临床医生诊断的 1 型糖尿病通过一种或多种胰岛特异性自身抗体阳性得到证实。在英国生物银行 ( n = 2502)，我们使用泊松回归估计了每个 HLA 组的 1 型糖尿病发病率相对于基线 HLA 风险的情况。分析仅限于欧洲白人，并根据 1 型糖尿病发病年龄分为三组：0-18 岁、19-30 岁和 31-50 岁。

结果

DR15-DQ6 在 50 岁之前都能预防 1 型糖尿病（每个年龄组的 OR < 1，所有p < 0.001）。在 ADDRESS-2 中观察到，相对于中性 HLA 基因型，1 型糖尿病的 OR 如下：年龄 5-18 岁 OR 0.16（95% CI 0.08，0.31）；年龄 19-30 岁或 0.10 (0.04, 0.23)；年龄 31-50 岁或 0.37 (0.21, 0.68)。在英国生物银行中，DR15-DQ6 在所有年龄段也保持高度保护性。如果没有 DR15-DQ6，主要 1 型糖尿病高风险单倍型（DR3-DQ2 或 DR4-DQ8）的存在与 1 型糖尿病风险增加相关。