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

2型糖尿病是一种高度遗传的疾病，但只有一小部分的遗传风险得到了解释。一种新的与2型糖尿病风险增加相关的遗传标记被发现，它比迄今为止发现的任何基因都要高得多。该遗传标记位于TCF7L2基因中。确定这种遗传标记是如何增加2型糖尿病风险的，可能对估计有8%的风险等位基因纯合子和患这种疾病的高风险人群的早期诊断和预防产生重大影响。根据PA-060155糖尿病内分泌与代谢探索性资助计划，本修订R21申请的目的是确定TCF7L2基因中的遗传标记改变2型糖尿病个体风险的机制。我们实验室新的初步数据表明，风险等位基因与TCF7L2表达的变化无关，而是与TCF7L2在分泌细胞中的定位改变有关。这与新的证据一致，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TCF7L2缺失的小鼠中，肠道中没有分泌神经内分泌细胞，进一步表明TCF7L2与分泌细胞之间存在联系。肠道和胰腺中的内分泌和神经内分泌细胞是独一无二的，因为它们拥有一个受调节的分泌系统，可以对葡萄糖的稳态进行微调。与2型糖尿病风险高度相关的TCF7L2 SNP rs7903146最近也与非糖尿病个体的胰岛素分泌减少有关，从而提供了更多的机制见解，即该缺陷本质上是分泌性的。在与Broad研究所的合作中，我们将结合使用新的方法和资源，包括人类组织基因分型、TCF7L2缺失小鼠模型和直接功能的获得和丧失实验，来验证与2型糖尿病风险高度相关的SNP （rs7903146）与结肠和胰腺分泌细胞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：

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.