IMPROVING PREDICTION OF IDDM

这项拟议的研究将调查相关的胰岛细胞自身抗体、人类白细胞抗原标记物和一个新的潜在的IDDM易感基因座(基因ICA1的多态性)在同一地理区域最大的基于人群的亲属队列中的作用，无论是否有IDDM。样本量小，后续研究有限，缺乏先进技术，限制了该领域以往的研究。这将是第一次有可能利用新的胰岛自身抗体分析来确定转化为IDDM的风险，并与旧的细胞质ICA分析在这一特定人群中估计的风险进行比较。近年来，应用分子生物学技术，已鉴定出一种与糖尿病相关的69 kDa多肽自身抗原--胰岛细胞自身抗原69 kDa(ICA69)和新抗原ICA12。目前，最新的数据表明，两种最流行的检测GAD65和IA-2自身抗体的生化方法不足以预测IDDM。拟议的项目计划优化生化分析，以检测与下列人类胰岛自身抗原反应的自身抗体：GAD65、IA-2、胰岛素、ICA69和ICA12。这5种重组自身抗原均可用于抗体筛选。这项研究将在匹兹堡中心进行，该中心目前有78名亲属，他们在预期的后续治疗中转换为IDDM(转化者)，超过5500名亲属。到此授权期结束时，将有大约100台转换器可供使用。这是所有中心中最多的转换器数量。此外，我们还收集了IDDM患者亲属的DNA，在我们的资料库中有完整的单链和多链家族的样本，其中有糖尿病兄弟姐妹和未受影响的兄弟姐妹。这是一套独特的血清和DNA样本，用于检验免疫学和遗传学假说。拟议的调查结果将有助于在普通人群中应用抗体和人类白细胞抗原-DQ和-DR标志物筛查IDDM，并在旨在预防IDDM的干预试验中进行IDDM风险评估。

The proposed research will investigate the role of relevant islet cell autoantibody, HLA markers, and a novel potential IDDM susceptibility genetic locus (polymorphism of the gene ICA1), in the largest population-based cohort of relatives, with and without IDDM, from the same geographical area. Small sample sizes, limited follow-up and the lack of advanced technology have limited previous studies in this field. For the first time, it will be possible to determine the risk of conversion to IDDM utilizing new islet autoantibody assays and compare with that estimated by the old cytoplasmic ICA assay in this specific population. Over the past few years, molecular biology techniques have been applied and a diabetes-related 69 kDa peptide autoantigen named Islet Cell Autoantigen 69 kDa (ICA69) and the novel antigen ICA12 were identified. Presently, recent data indicate that the two most popular biochemical assays for detecting autoantibodies to GAD65 and IA-2 are not sufficient for predicting IDDM. The proposed project plans to optimize biochemical assays for detecting autoantibodies reacting with the following human islet autoantigens: GAD65, IA-2, insulin, ICA69 and ICA12. These 5 recombinant autoantigens are accessible for antibody screening. This research will be performed at the Pittsburgh center which currently has 78 relatives, who converted to IDDM during a prospective follow-up (converters), from a pool of over 5,500 relatives. Approximately 100 converters will be available by the end of this grant period. This represents the largest number of convertors for any center. Also, DNA has been collected from relatives of IDDM patients, and we have specimens on complete simplex and multiplex families with diabetic and unaffected siblings in our repository. This is a unique set of serum and DNA samples for the testing of immunologic and genetical hypotheses. The outcome of the proposed investigation should facilitate the stage for the application of antibody and HLA-DQ and -DR markers in the screening for IDDM in the general population and for risk assessment for IDDM in intervention trials intended to prevent IDDM.