IMPROVING PREDICTION OF IDDM

拟议的研究将调查相关的胰岛细胞自身抗体、HLA标记物和一种新的潜在IDDM易感性遗传位点（基因ICA1多态性）在最大的基于人群的亲属队列中的作用，无论是否患有IDDM，来自同一地理区域。样本量小、随访有限以及缺乏先进技术限制了这一领域先前的研究。在这一特定人群中，首次有可能利用新的胰岛自身抗体测定方法来确定转化为IDDM的风险，并与旧的细胞质ICA测定方法进行比较。近年来，利用分子生物学技术鉴定出了一种与糖尿病相关的69 kDa肽自身抗原——胰岛细胞69 kDa （Islet Cell autoantigen 69 kDa, ICA69）和新抗原ICA12。目前，最近的数据表明，用于检测GAD65和IA-2自身抗体的两种最流行的生化检测方法不足以预测IDDM。本项目拟优化与以下胰岛自身抗原反应的自身抗体的生化检测方法：GAD65、IA-2、胰岛素、ICA69和ICA12。这5种重组自身抗原可用于抗体筛选。这项研究将在匹兹堡中心进行，该中心目前有78名亲属，他们在未来的随访中转换为IDDM（转换者），来自5500多名亲属。到本赠款期结束时，将提供大约100台转换器。这代表了任何中心转换器的最大数量。此外，我们还收集了IDDM患者亲属的DNA，并且在我们的存储库中有糖尿病和未患病兄弟姐妹的完全单纯性和多重性家庭的标本。这是一套独特的血清和DNA样本，用于免疫学和遗传学假设的测试。拟议的调查结果应促进抗体和HLA-DQ和-DR标记物在普通人群中筛查IDDM以及在旨在预防IDDM的干预试验中用于IDDM风险评估的应用阶段。

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.