权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Genetics of Type 2 Diabetes

2 型糖尿病的遗传学

基本信息

批准号：
8020597
负责人：
Steven C Elbein
金额：
$ 5.4万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8020597
关键词：
1q21 1q21-q23 Abbreviations Accounting Acute Address Adipocytes Adipose tissue African American Allelic Imbalance Amish Arkansas Biological Candidate Disease Gene Caucasians Caucasoid Race Cells Chinese People Chromosomes Chromosomes, Human, Pair 1 Clinical Research Complement Complex Data Defect Disease Equilibrium Ethnic group European Event Family Study Fatty acid glycerol esters Funding Gene Expression Gene Expression Alteration Gene Frequency Genes Genetic Genetic Predisposition to Disease Genome Scan Genomics Glucose Haplotypes Hepatic Individual Insulin International Laboratories Lead Leukocytes Linkage Disequilibrium Liver Lymphocyte Maps Mediating Methods MicroRNAs Minor Modeling Molecular Muscle Neuraxis Non-Insulin-Dependent Diabetes Mellitus Organ Pancreas Pathogenesis Pathway interactions Peripheral Physiological Pima Indian Population Predisposition Pyruvate Kinase Reporting Research Design Research Personnel Role Sampling Signal Transduction Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Single Nucleotide Polymorphism in Regulatory Sequence Susceptibility Gene Tandem Repeat Sequences Testing Tissues United States National Institutes of Health Untranslated RNA Untranslated Regions Utah Variant base caucasian American genome wide association study glucose production glucose uptake human subject impaired glucose tolerance indexing insulin secretion insulin sensitivity intravenous glucose tolerance test member non-diabetic novel programs research study response trait

项目摘要

DESCRIPTION (provided by applicant): This ongoing project previously demonstrated linkage of type 2 diabetes (T2DM) to chromosome 1q21-q24 in Caucasians, and more recently in African American subjects. Data from the last funding period show convincingly that although replicating well across ethnic groups, the 1q linkage region encompasses multiple susceptibility loci, and that these loci interact with other chromosomal regions in Caucasians. Furthermore, data from our laboratory and others suggest that most susceptibility variants will be noncoding. Based on these findings, we propose several hypotheses. 1) Multiple 1q loci of varying effect size contribute to the linkage signal, and 2) at least some loci will be unique to each population. 3) These susceptibility variants will alter gene expression or noncoding RNA in key physiologic pathways, and 4) some subset of these loci can be detected by alteration of gene expression in available tissues (fat, lymphocytes, and muscle). 5) Chromosome 1 loci will interact with each other and with non-chromosome 1 susceptibility loci to increase T2DM susceptibility. We propose 5 aims to test these hypotheses. Our studies are designed to complement NIH funded international, high throughput efforts to localize 1q susceptibility loci by providing physiologic and lower throughput approaches for regions of significance in our populations. In Aims 1 and 2, we will use dense maps, allelic association, family studies, and intermediate trait studies to extend initial findings from our laboratory and the Consortium in Caucasian and African American samples. Aim 3 will test for interactions both among chromosome 1 loci and between the strongest 1q loci and regions on other chromosomes, particularly non-1 q loci with evidence for association in other populations. Aim 4 will use novel methods to test for allelic imbalance in broadly defined candidate genes, suggesting nearby cis-acting regulatory variants, in adipocytes, muscle, and transformed lymphocytes obtained from Caucasian and African American human subjects. Aim 5 will initiate studies to identify the physiologic consequences of the most strongly associated variants, including gene expression in adipocytes and muscle. Together with ongoing efforts from the Consortium and other laboratories, we expect these studies will localize and begin to characterize the specific variants that increase susceptibiltiy to T2DM in two populations, and will lead to additional studies to identify the biological pathways involved in T2DM pathogenesis.

描述（由申请人提供）：该正在进行的项目先前证明了高加索人2型糖尿病（T2 DM）与染色体1 q21-q24的联系，最近在非洲裔美国人受试者中也有。上一个资助期的数据令人信服地表明，尽管在不同种族群体中复制良好，但1 q连锁区包含多个易感基因座，并且这些基因座与高加索人的其他染色体区域相互作用。此外，来自我们实验室和其他实验室的数据表明，大多数易感性变异将是非编码的。基于这些发现，我们提出了几个假设。1)不同效应大小的多个1 q基因座有助于连锁信号，2）至少一些基因座对每个群体是独特的。3)这些易感性变体将改变关键生理途径中的基因表达或非编码RNA，以及4）这些位点的某些子集可以通过改变可用组织（脂肪、淋巴细胞和肌肉）中的基因表达来检测。5)1号染色体基因座之间以及与非1号染色体易感基因座之间会相互作用，从而增加T2 DM的易感性。我们提出了5个目标来验证这些假设。我们的研究旨在补充NIH资助的国际高通量工作，通过为我们人群中的重要区域提供生理和低通量方法来定位1 q易感基因座。在目标1和2中，我们将使用密集图谱、等位基因关联、家族研究和中间性状研究来扩展我们实验室和联盟在高加索人和非裔美国人样本中的初步发现。目标3将测试1号染色体基因座之间的相互作用，以及最强的1 q基因座和其他染色体上的区域之间的相互作用，特别是非1 q基因座与其他群体中的关联证据之间的相互作用。目标4将使用新的方法来测试广泛定义的候选基因中的等位基因不平衡，这表明附近的顺式作用调节变体，在从高加索人和非洲裔美国人受试者获得的脂肪细胞，肌肉和转化的淋巴细胞中。目标5将启动研究，以确定最强烈的相关变异的生理后果，包括脂肪细胞和肌肉中的基因表达。与联盟和其他实验室的持续努力一起，我们预计这些研究将定位并开始表征在两个人群中增加T2 DM易感性的特定变体，并将导致更多的研究来确定T2 DM发病机制中涉及的生物学途径。