IMMUNOLOGICAL CANDIDATE GENES FOR IDDM SUSCEPTIBILITY

描述(摘自申请者摘要)：胰岛素依赖型糖尿病 糖尿病(IDDM)是一种自身免疫性疾病，由细胞 胰岛细胞的浸润和破坏。发生的事件 启动这一致病过程的人知之甚少。这一趋势 IDDM在家庭中聚集和35%-40%的符合率 同卵双胞胎表明遗传和环境因素 增加IDDM的易感性。它已经被公认了20多年了 人类白细胞抗原区域的一个或多个基因在人类基因组中起重要作用的年份 IDDM的发展。然而，IDDM在家庭内的隔离符合 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。试图了解潜在的原因 对于IDDM，人们一直在寻找人类基因组中 证明与IDDM有遗传关联。除了人类白细胞抗原，还有一个额外的区域 在有强烈暗示的证据表明存在联系和 其他六个地区，至少有适度的证据值得进一步研究。 然而，像这样的连锁方法，它们检测等位基因在 受影响的同胞对，只有有限的能力来检测范围内的基因 对人类白细胞抗原以外的IDDM易感基因的预期影响。 相比之下，联想研究确实有这样的力量，但在过去 经常受到样本量小、研究设计不充分以及 范围有限。更新的资源和技术现在的可用性 使这种方法在更大的范围内适用。此应用程序 建议评估100个或更多候选基因的作用，其产物 可能与免疫系统功能有关的IDDM 易感基因。通过以分子为目标进行研究，因为 它们在免疫系统中的功能作用可能被识别出来 与IDDM相关但本应消失的IDDM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多发性家庭的优势， 密集的遗传图谱，将高度多态的标记放置在大多数候选标记附近 基因，更强大的基于家庭的检测关联的方法，以及 高通量基因分型技术来分析这大量的选择 单一研究中的候选免疫系统基因。IDDM的识别 敏感度 通过这种方法获得的基因应该为免疫研究提供重要的见解。 在IDDM中被破坏的通路，并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.