Type 1 Diabetes Genetics Consortium

本申请请求支持建立“1型糖尿病遗传联盟”。的目标是 该联盟将组织国际努力，以确定决定个人患1型糖尿病风险的基因。 提出了特征良好的家系的资源库，这将有助于类型1的本地化和特征化 决定疾病风险的糖尿病基因。统计遗传分析将确定这些区域的行为方式，以便 促进地图绘制和本地化。使用联盟资源，联盟的成员和合作者将 进行位置克隆，以确定决定易感性或保护性的单个基因。基于当前 对三个完整的基因组筛查进行分析，非人类白细胞抗原区域基因可能单独贡献相对较小(但是 显著增加遗传风险(Xs~1.12-1.30)。电力分析表明，-4300个受影响的兄弟姐妹家庭将 被要求达到90%的权力，以提示证据的连锁在这些特定的风险水平。当前 基因组扫描数据存在于1200个家庭。超过600个受影响的同胞对家庭有样本等待基因组扫描 其他收藏(联合王国、芬兰、HBDI、澳大利亚和撒丁岛)，以及对这些收藏进行基因组扫描的请求 家庭已提交给CDDR。为了达到4300个受影响的同胞对家庭进行连锁的目标，一个新的 需要收集2500个受影响的同胞对家庭。 为了建立这个由4300个家庭组成的综合资源，并对 针对1型糖尿病的易感基因，提出了一系列针对性的研究目标，以充分利用和更新现有资料 并收集新的临床资源。本研究的具体目的是(1)重新确定2500个受影响的同胞对 家庭通过欧洲网络(1200)、澳大拉西亚网络(200)和美国网络(1100)使用标准化 方案；(2)采集外周血并建立淋巴母细胞系(LCL)，以提供可再生的来源 基因组DNA、RNA、蛋白质和细胞，使未来的免疫功能研究成为可能；(3)人类白细胞抗原II类和I类基因 基因(DRB1、DQB1、DPB1、DPA1、A、B、C)、INS和CTLA4基因多态是公认的1型糖尿病遗传风险 各种因素。(4)利用现有的单基因家系(Trio，包括未受影响的兄弟姐妹)进行疾病关联分析 如果可用)以及病例和对照；(5)使用基于信息的(单倍型标记的)SNPs图来 系统和有效地改进用于检测1型糖尿病基因座的位置。进一步的遗传分析以确定和 确认候选基因(使用单倍型标记的SNPs)将需要财团实验室和 使用联盟材料(DNA、数据)的补充支持。 这项应用的最终目标是提供基本的临床和遗传资源，以实现 基因鉴定所需的样本量和样本量。财团将建立一个机制，以 确保科学家们将共同努力，更好地了解导致1型癌症风险的遗传因素 糖尿病。该联盟将更好地了解疾病的机制，目的是改变这些 1型糖尿病风险的个体机制和途径。

This applicationrequests support to establish the "Type 1Diabetes GeneticsConsortium". The goal of the Consortium is to organize internationalefforts to identify genes that determinean individual's risk for type 1 diabetes.A resource base of well-characterized families is proposed that will facilitatethe localization and characterizationof type 1 diabetes genes that determine disease risk. Statistical genetic analyses will determinehow these regions act in order to facilitate mapping and localization. Using the Consortium resources, members and collaborators of the Consortium will undertake positional cloning to identify individual genes that determine susceptibility or protection. Based upon current analyses of three completed genome screens, non-HLA region genes may individuallycontribute relatively small (but significant) increments in genetic risk (Xs ~ 1.12-1.30). Power analyses suggest that -4300 affected sib-pair families will be required to achieve 90% power for suggestive evidence for linkage at these levels of locus-specific risk. Current genome scan data exist on -1200 families. Over 600 affected sib-pair families have samples waiting genome scanning in other collections (United Kingdom, Finland, HBDI, Australia and Sardinia), and a request for the genome scan on these families has been submitted to CDDR. In order to meet the target of 4300 affected sib-pair families for linkage, a new collection of 2500 affected sib-pair families is required. In order to establish this combined resource of 4300 familiesand to carry out an appropriately powered search for type 1diabetes susceptibility genes, a series of specific aims are proposed to fully utilize and update existing materials and to collect new clinical resources. The specific aims of this study are to (1) newly ascertain 2500 affected sib-pair families through a European network (1200), an Australasian network (200), and a US network (1100) using standardized protocols; (2) collect, peripheral blood and establish lymphoblastoid cell lines (LCLs) to provide a renewable source of genomic DNA, RNA, protein and cells, to enable future studies of immune function; (3) genotype HLA class II and class I genes (DRB1, DQB1, DPB1, DPA1, A, B, C), INS, and CTLA4polymorphisms as recognized type 1diabetes genetic risk factors. (4) carry out disease association analyses using existing singlecase families (trios, includingan unaffected sibling when available) and cases and controls; (5) use an informativehaplotype-based map of (haplotype-tagged) SNPs to systematically and efficiently refine locations for detectingtype 1 diabetes loci. Further geneticanalyses to identify and confirm candidate genes (using haplotype-tagged SNPs) will require joint investigation by Consortium laboratories and supplemental support using Consortium material (DNA, data). The ultimate goal of this application is to provide the fundamental clinical and genetic resources to achieve the necessary sample size and sample availability for gene identification. The Consortium will establish a mechanism to ensure that scientists will work together toward a better understanding of the genetic factors that underlie risk of type 1 diabetes. The Consortium will gain a better understandingof disease mechanisms, with a purpose of altering these mechanisms and pathways in individualsat risk of type 1 diabetes.