Defining How a Variant in TCF7L2 Confers Increased Risk for Type 2 Diabetes

描述（申请人提供）：摘要2型糖尿病是一种高度遗传性疾病，但只有一小部分的整体遗传风险已被解释。一种与2型糖尿病风险增加相关的新遗传标记被发现，它比迄今为止发现的任何基因都要危险得多。该遗传标记位于TCF 7 L2基因中。确定这种遗传标记如何增加2型糖尿病的风险可能对估计8%的人群的早期诊断和预防产生重大影响，这些人群是风险等位基因纯合子，并且具有这种疾病的高风险。本修订版R21申请旨在响应PA-060155糖尿病内分泌学和代谢探索性资助计划，旨在确定TCF 7 L2基因中的遗传标记改变2型糖尿病个体风险的机制。我们实验室的新的初步数据表明，风险等位基因与TCF 7 L2表达的变化无关，而是与分泌细胞中TCF 7 L2的定位改变有关。这与新的证据相吻合，即风险等位基因的纯合性与分泌蛋白嗜铬粒蛋白A的表达增加有关。有趣的是，在TCF 7 L2基因敲除小鼠中，肠道中的分泌性神经内分泌细胞不存在，进一步表明TCF 7 L2和分泌细胞之间的联系。肠道和胰腺中的内分泌细胞和神经内分泌细胞是独特的，因为它们具有调节分泌系统，该系统允许对葡萄糖稳态进行微调。与2型糖尿病风险最高度相关的TCF 7 L2 SNP rs7903146最近也与非糖尿病个体的胰岛素分泌减少相关，从而提供了更多的机制见解，即缺陷本质上是分泌性的。与Broad研究所合作，我们将使用新方法和资源的组合，包括基因分型的人类组织，TCF 7 L2 null小鼠模型，以及直接获得和功能丧失实验，以检验与2型糖尿病风险最高度相关的SNP（rs7903146）与结肠和胰腺分泌细胞中的原发性缺陷相关的假设。如果这些发现得到证实，这一发现可能会对估计8%的风险等位基因纯合子人群和2型糖尿病高风险人群产生重大影响。我们提出以下目标： I.确定与SNP（rs7903146）相关的结肠和胰腺中TCF 7 L2的定位、表达或剪接的改变，该SNP赋予2型糖尿病最大的风险。 二.确定TCF 7 L2（rs7903146）中风险等位基因的纯合性（TT）与结肠和胰腺分泌细胞群的缺陷相关。预计到2030年，全球糖尿病患者人数将从1.71亿增加到3.66亿。2型糖尿病是一种高度遗传性疾病，但只有一小部分的整体遗传风险的疾病已被解释。然而，最近的一项发现确定了TCF 7 L2基因的突变，这导致了患2型糖尿病的风险更大。本R21申请项目公告（糖尿病、内分泌和代谢探索性资助项目）的目的是解释TCF 7 L2基因突变如何改变生物功能并增加2型糖尿病的风险。长期目标是了解导致2型糖尿病的基本机制，并利用这些信息来改善医疗保健。

DESCRIPTION (provided by applicant): ABSTRACT Type 2 diabetes is a highly heritable disease, yet only a small fraction of overall genetic risk has been explained. A new genetic marker associated with increased risk for type 2 diabetes has been found that accounts for a much greater risk than any gene identified to date. This genetic marker is in the TCF7L2 gene. Identification of how this genetic marker increases risk for type 2 diabetes could have a major impact on early diagnosis and prevention for the estimated 8% of the population that is homozygous for the risk allele and at high risk for this disease. The goal of this revised R21 application in response to PA-060155 Exploratory Grant Program in Diabetes Endocrinology and Metabolism is to determine the mechanism(s) through which a genetic marker in the TCF7L2 gene modifies individual risk for type 2 diabetes. New preliminary data from our lab suggests that the risk allele is not associated with a change in TCF7L2 expression but rather with altered localization of TCF7L2 in secretory cells. This coincides with new evidence that homozygosity for the risk allele is associated with increased expression of the secretory protein Chromogranin A. Interestingly, secretory neuroendocrine cells in the gut are absent in the TCF7L2 null mice, further suggesting a link between TCF7L2 and secretory cells. Endocrine and neuroendocrine cells in the gut and pancreas are unique in that they possess a regulated secretory system that allows for the fine tuning of glucose homeostasis. The TCF7L2 SNP rs7903146 most highly associated with risk of type 2 diabetes has also recently been associated with reduced insulin secretion in non-diabetic individuals, thereby providing more mechanistic insight that the defect is secretory in nature. In collaboration with the Broad Institute we will use a combination of novel approaches and resources including genotyped human tissue, the TCF7L2 null mouse model, and direct gain and loss of function experiments to test the hypothesis that the SNP most highly associated with risk of type 2 diabetes (rs7903146) is associated with a primary defect in the secretory cells in the colon and pancreas. If these findings are confirmed, this discovery could have significant impact on the estimated 8% of the population that is homozygous for the risk allele and at high risk for type 2 diabetes. We propose the following aims: I. Identify alterations in localization, expression, or splicing of TCF7L2 in the colon and pancreas associated with the SNP (rs7903146) that confers greatest risk for type 2 diabetes. II. Establish that homozygosity (TT) for the risk allele in TCF7L2 (rs7903146) is associated with a defect in the secretory cell population in the colon and pancreas.The number of people with diabetes in the world is projected to rise from 171 million to 366 million by year 2030. Type 2 diabetes is a highly heritable disease, yet only a small fraction of overall genetic risk of the disease has been explained. However, a recent discovery identified mutations in the gene, TCF7L2, that account for a much greater risk of developing type 2 diabetes. The purpose of this R21 application for Program Announcement (Exploratory Grant Program in Diabetes and Endocrinology and Metabolism) is to translate how a mutation in the TCF7L2 gene alters biological function and increases risk for type 2 diabetes. The long term goal is to understand basic mechanisms leading to type 2 diabetes and use this information to improve health care.