IMPROVING PREDICTION OF IDDM

该研究将调查相关胰岛细胞自身抗体、HLA标记物和一种新的潜在的IDDM易感基因位点（ICA 1基因多态性）在同一地理区域最大的人群亲属队列中的作用，包括有或无IDDM。 样本量小，随访有限，缺乏先进的技术限制了这一领域的研究。 这是第一次，它将有可能确定转化为胰岛素依赖型糖尿病的风险，利用新的胰岛自身抗体测定，并与旧的细胞质伊卡测定估计在这个特定的人群。 过去几年，分子生物学技术的应用，鉴定出了一种与糖尿病相关的69 kDa肽自身抗原，命名为胰岛细胞自身抗原69 kDa（ICA 69）和新抗原ICA 12。 目前，最近的数据表明，两个最流行的生化检测GAD 65和IA-2的自身抗体是不足以预测IDDM。 拟议项目计划优化用于检测与以下人类胰岛自身抗原反应的自身抗体的生化测定：GAD 65、IA-2、胰岛素、ICA 69和ICA 12。 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，他们在前瞻性随访期间从5,500多名亲属中转化为IDDM。 大约100个转换器将在本赠款期结束时提供。 这代表了任何中心转换器的最大数量。 此外，DNA已收集从亲属的胰岛素依赖型糖尿病患者，我们有标本的完整的单一和多重家庭与糖尿病和未受影响的兄弟姐妹在我们的知识库。 这是一组独特的血清和DNA样本，用于检测免疫学和遗传学假设。 建议的调查结果应促进阶段的抗体和HLA-DQ和-DR标记物的应用程序中筛选的胰岛素依赖型糖尿病在一般人群和胰岛素依赖型糖尿病的风险评估的干预试验，旨在防止胰岛素依赖型糖尿病。

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.