Type 1 Diabetes Genetics Consortium

描述(由申请人提供)： 这个应用程序请求支持建立“1型糖尿病遗传联盟”。该联盟的目标是组织国际努力，以确定决定个人患1型糖尿病风险的基因。提出了一个特征良好的家系的资源库，这将促进决定疾病风险的1型糖尿病基因的定位和表征。统计遗传分析将确定这些区域如何行动，以促进绘图和本地化。利用该联盟的资源，该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。根据目前对三个完整基因组筛查的分析，非人类白细胞抗原区域基因可能单独对遗传风险贡献相对较小(但显著)的增量(S 1.12-1.30)。力量分析表明，4300个受影响的同胞对家庭将被要求达到90%的力量，以提示在这些特定座位风险水平上的连锁证据。目前有1200个家庭的基因组扫描数据。600多个受影响的同胞对家庭在其他收集中有等待基因组扫描的样本(英国、芬兰、HBDI、澳大利亚和撒丁岛)，已向CIDR提交了对这些家庭进行基因组扫描的请求。为了达到4300个受影响的同胞对家庭进行连锁的目标，需要新收集2500个受影响的同胞对家庭。 为了建立这个由4300个家系组成的联合资源，并对1型糖尿病易感基因进行适当有力的搜索，提出了一系列具体目标，以充分利用和更新现有资料，收集新的临床资源。这项研究的具体目标是：(1)通过欧洲网络(1200)、澳大利亚网络(200)和美国网络(1100)，使用标准化的协议来新确定2500个受影响的同胞对家庭；(2)收集外周血并建立淋巴母细胞系(LCL)，以提供可再生的基因组DNA、RNA、蛋白质和细胞来源，以便将来对免疫功能的研究；(3)HLA型？那阶级呢？基因(DRB1、DQB1、DPB1、DPAI、A、B、C)、INS和CTLA4基因多态是公认的1型糖尿病遗传危险因素。(4)利用现有的单一病例家系(三个，如果有的话，包括一个未受影响的兄弟姐妹)以及病例和对照进行疾病关联分析；(5)使用基于信息的单倍型(单倍型标记)SNPs图谱，系统和有效地改进检测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)将需要联盟实验室的联合调查和使用联盟材料(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，以实现必要的样本大小和样本可用性，以进行基因鉴定。该联盟将建立一种机制，以确保科学家们共同努力，更好地了解导致1型糖尿病风险的遗传因素。该联盟将更好地了解疾病机制，目的是改变1型糖尿病风险人群的这些机制和途径。

DESCRIPTION (provided by applicant): This application requests support to establish the "Type 1 Diabetes Genetics Consortium". The goal of the Consortium is to organize international efforts to identify genes that determine an individual's risk for type 1 diabetes. A resource base of well-characterized families is proposed that will facilitate the localization and characterization of type 1diabetes genes that determine disease risk. Statistical genetic analyses will determine how 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 individually contribute relatively small (but significant) increments in genetic risk (?s ?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 CIDR. 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 families and to carry out an appropriately powered search for type 1 diabetes 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 ?? and class ? genes (DRB 1, DQB 1, DPB 1, DPAI, A, B, C), INS, and CTLA4 polymorphisms as recognized type 1 diabetes genetic risk factors. (4) carry out disease association analyses using existing single case families (trios, including an unaffected sibling when available) and cases and controls; (5) use an informative haplotype based map of (haplotype-tagged) SNPs to systematically and efficiently refine locations for detecting type 1 diabetes loci. Further genetic analyses 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 understanding of disease mechanisms, with a purpose of altering these mechanisms and pathways in individuals at risk of type 1 diabetes.