Type 1 Diabetes Genetics Consortium

描述（由申请人提供）： 本申请请求支持建立“1型糖尿病遗传学联盟”。该联盟的目标是组织国际努力，以确定决定个人1型糖尿病风险的基因。提出了一个具有良好特征的家族资源库，这将有助于确定疾病风险的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发挥作用，以促进绘图和定位。利用联盟的资源，联盟的成员和合作者将进行定位克隆，以确定决定易感性或保护的单个基因。基于目前对三个完整的基因组筛查的分析，非HLA区域基因可能单独贡献相对较小（但显着）的遗传风险增量（？）s？1.12-1.30）。权力分析表明，？4300个受影响的同胞对家庭将需要达到90%的权力，在这些水平的基因座特异性风险的联系的提示性证据。目前的基因组扫描数据存在于1200个家庭。600多个受影响的同胞对家庭的样本在其他收集地（联合王国、芬兰、HBDI、澳大利亚和撒丁岛）等待基因组扫描，已向CIDR提交了对这些家庭进行基因组扫描的请求。为了满足4300个受影响的同胞对家庭的连锁目标，需要新收集2500个受影响的同胞对家庭。 为了建立这4300个家庭的联合资源，并进行适当的动力搜索1型糖尿病易感基因，提出了一系列具体的目标，充分利用和更新现有的材料，并收集新的临床资源。本研究的具体目的是：（1）通过欧洲网络（1200）、澳大利亚网络（200）和美国网络（1100），使用标准化协议，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样细胞系（LCL）以提供基因组DNA、RNA、蛋白质和细胞的可再生来源，（3）HLA基因型分类？？阶级？基因（DR B 1、DQ B 1、DPB 1、DPAI、A、B、C）、INS和CTLA 4多态性作为公认的1型糖尿病遗传风险因子。(4)使用现有的单个病例家族（三人组，包括未受影响的同胞，当可用时）和病例和对照进行疾病关联分析;（5）使用基于单倍型的（单倍型标记的）SNP图谱的信息，以系统地和有效地细化用于检测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SNP）将需要联合实验室的联合调查和补充支持，使用财团材料（DNA，数据）。 本申请的最终目标是提供基本的临床和遗传资源，以达到基因鉴定所需的样本量和样本可用性。该联盟将建立一个机制，以确保科学家们共同努力，更好地了解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，目的是改变有1型糖尿病风险的个体的这些机制和途径。

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.