Hermann Róbert, Soltész Gyula
Pécsi Tudományegyetem, Altalános Orvostudományi Kar, Gyermekklinika, Pécs.
Orv Hetil. 2004 Feb 15;145(7):337-42.
In the modern genetic era the principles of genetic screening are being changed. In addition to diagnostic screening for rare monogenic diseases, predictive screening for common polygenic conditions, like type 1 diabetes, will be more widely implemented. The majority of the genetic background of type 1 diabetes is encoded by the HLA DQ and DR genes, selected variants of which could be used as screening markers. However, risk conferred by various HLA genotypes shows considerable ethnic variation, therefore population-specific screening markers need to be established.
The aim of this study was to describe a screening strategy based on risk-defining HLA DRB1-DQA1-DQB1 markers to identify individuals at risk for type 1 diabetes in the Hungarian population.
HLA genotypes of 149 consecutively diagnosed children with type 1 diabetes (age at diagnosis 0-14, mean 8.8 +/- 4.2 years) and 177 randomly selected healthy schoolchildren were studied. Allele-specific polymerase chain reaction method was used for HLA typing. The diagnostic sensitivity, specificity and predictive value of diabetes associated DRB1-DQA1-DQB1 alleles were analysed in a step-wise strategy.
The highest diagnostic sensitivity was detected when DQB1 typing was complemented by DQA1 typing on DQB10201 positive samples with additional DRB104 subtyping in DQB10302 carriers. The combination of the following markers gave a relative risk of 28.9 (95% confidence interval: 15.9-52.7, p = 10(-6): DQB10201/0302-DQA10301,0501-b (b not equal to DRB1 0403), DQB10302/x-DRB10401,0402 (not equal to DQB10201, 0301,0602,0603), DQB10301/0302-DRB10401,0404, DQB10304/s (s = any DQB1 alleles), DQB10201/y-DQA10501/a (y not equal to DQB10301,0302,0602, 0603,0604, a not equal to DQA10201). The diagnostic sensitivity, specificity and positive predictive values for this marker combination were 79.2%, 88.7%, and 1.1%, respectively.
Using HLA DRB1-DQA1-DQB1 markers predictive genetic screening for type 1 diabetes is feasible in the Hungarian population with high diagnostic sensitivity and specificity. At present, such a screening for individuals at risk for type 1 diabetes in the general population is recommended only as part of prospective studies on the natural history or prevention of disease. To increase the positive predictive value of the model, pancreas beta-cell autoantibodies need to be measured and followed in the high-risk cohort.
在现代基因时代，基因筛查的原则正在发生变化。除了针对罕见单基因疾病的诊断性筛查外，针对常见多基因疾病（如1型糖尿病）的预测性筛查将得到更广泛的应用。1型糖尿病的大部分遗传背景由HLA DQ和DR基因编码，其特定变体可作为筛查标志物。然而，不同HLA基因型所赋予的风险存在相当大的种族差异，因此需要建立针对特定人群的筛查标志物。
本研究的目的是描述一种基于风险定义的HLA DRB1 - DQA1 - DQB1标志物的筛查策略，以识别匈牙利人群中1型糖尿病的高危个体。
研究了149例连续诊断的1型糖尿病儿童（诊断时年龄0 - 14岁，平均8.8±4.2岁）和177例随机选择的健康学童的HLA基因型。采用等位基因特异性聚合酶链反应方法进行HLA分型。采用逐步策略分析与糖尿病相关的DRB1 - DQA1 - DQB1等位基因的诊断敏感性、特异性和预测价值。
当在DQB10201阳性样本上进行DQA1分型，并在DQB10302携带者中进行额外的DRB104亚型分型来补充DQB1分型时，检测到最高的诊断敏感性。以下标志物组合的相对风险为28.9（95%置信区间：15.9 - 52.7，p = 10⁻⁶）：DQB10201/0302 - DQA10301,0501 - b（b不等于DRB10403），DQB10302/x - DRB10401,0402（不等于DQB10201, 0301,0602,0603），DQB10301/0302 - DRB10401,0404，DQB10304/s（s = 任何DQB1等位基因），DQB10201/y - DQA10501/a（y不等于DQB10301,0302,0602, 0603,0604，a不等于DQA10201）。该标志物组合的诊断敏感性、特异性和阳性预测值分别为79.2%、88.7%和1.1%。
使用HLA DRB1 - DQA1 - DQB1标志物对1型糖尿病进行预测性基因筛查在匈牙利人群中是可行的，具有较高的诊断敏感性和特异性。目前，仅建议将这种针对一般人群中1型糖尿病高危个体的筛查作为疾病自然史或预防前瞻性研究的一部分。为了提高模型的阳性预测值，需要在高危队列中检测并跟踪胰腺β细胞自身抗体。
