IMMUNOLOGICAL CANDIDATE GENES FOR IDDM SUSCEPTIBILITY

描述（改编自申请人摘要）：胰岛素依赖型糖尿病 胰岛素依赖型糖尿病（IDDM）是一种自身免疫性疾病， 胰岛细胞的浸润和破坏。 的事件 启动这一致病过程是知之甚少。 的倾向 胰岛素依赖型糖尿病在家庭中聚集， 同卵双胞胎表明遗传和环境因素 导致胰岛素依赖型糖尿病易感性。 它已经被认可了20多年 HLA区域中的一个或多个基因在人类免疫系统中起着重要作用。 糖尿病的发展。 然而，家庭内胰岛素依赖型糖尿病的隔离符合 没有简单的模式和其他基因对IDDM易感性的贡献 一直被怀疑。 为了试图了解潜在的原因 在胰岛素依赖型糖尿病中，人们一直在寻找人类基因组的区域， 与胰岛素依赖型糖尿病有遗传联系。 除了HLA，还有一个地区 在有强烈证据表明存在关联的情况下， 其他六个地区至少有适度的证据证明需要进一步研究。 然而，连锁方法，如这些，分析等位基因共享， 受影响的同胞对，只有有限的权力，以检测基因的范围 对除HLA以外的IDDM易感基因的预期影响。 相比之下，关联研究确实具有这种力量，但在过去， 通常受到样本量小、研究设计不足和 有限的范围。 现在有了新的资源和技术， 使这种方法在更大的范围内适用。 本申请 建议评估100个或更多候选基因的作用， 可能与胰岛素依赖型糖尿病的免疫系统功能有关 易感基因 通过针对分子进行研究， 它们在免疫系统中的功能作用， 与胰岛素依赖型糖尿病相关的胰岛素依赖型糖尿病易感基因 在遗传连锁的筛查中未被发现。 调查人员将采取 充分利用616个IDDM多发家系的实际收集， 将高度多态性标记放置在大多数候选者附近的密集遗传图谱 基因，更强大的基于家庭的方法来检测关联， 高通量基因分型技术来分析这一大的选择， 候选的免疫系统基因。 IDDM的鉴别 易感性 通过这种方法，基因应该为免疫学提供重要的见解。 在胰岛素依赖型糖尿病中被破坏的通路，可能提示新的预防或 治疗方法。

DESCRIPTION (adapted from applicant's abstract): Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder which results from cellular infiltration and destruction of the pancreatic islet cells. The events that initiate this pathogenic process are poorly understood. The tendency of IDDM to cluster in families and the 35-40 percent concordance rate in identical twins suggest that both genetic and environmental factors contribute to IDDM susceptibility. It has been recognized for more than 20 years that a gene or genes in the HLA region plays a significant role in the development of IDDM. However, the segregation of IDDM within families fits no simple pattern and the contribution of other genes to IDDM susceptibility has long been suspected. In an attempt to understand the underlying causes of IDDM, there has been a search for regions of the human genome that demonstrate genetic linkage to IDDM. Besides HLA, one additional region has been identified where there is strongly suggestive evidence of linkage and six other regions with at least modest evidence warranting further study. However, linkage approaches such as these, which assay allele sharing in affected sib pairs, have only limited power to detect genes with the range of effects expected for IDDM susceptibility genes other than HLA. Association studies, in contrast, do have such power, but in the past have often been hindered by small sample sizes, inadequate study designs, and limited scope. The availability of newer resources and technologies now make this approach applicable on a much larger scale. This application proposes to evaluate the role of 100 or more candidate genes whose products are specifically involved in immune system function as possible IDDM susceptibility genes. By targeting molecules for investigation because of their functional role in the immune system it may be possible to identify IDDM susceptibility genes that are associated with IDDM but would have gone undetected in a screen for genetic linkage. Investigators will take advantage of the substantial collection of 616 IDDM multiplex families, dense genetic maps that place highly polymorphic markers near most candidate genes, more robust family-based methods for detecting associations, and high-throughput genotyping techniques to analyze this large selection of candidate immune system genes in a single study. Identification of IDDM susceptibility genes by such an approach should provide important insights into immune pathways that are disrupted in IDDM and may suggest novel preventative or therapeutic approaches.