The JAZF1 Gene and Type 2 Diabetes

描述(由申请人提供)：涉及整个人类基因组的单核苷酸多态(SNPs)调查的研究最近发现JAZF1基因第一外显子的SNP与2型糖尿病患者有关。这种联系的生物学基础尚不清楚。此外，人们对该基因的总体功能知之甚少。它的蛋白产物存在于大多数人类细胞中，并位于细胞质和细胞核中。JAZF1的5‘端是存在于子宫内膜间质肿瘤中的基因融合的一部分，从该基因转录的前mRNA参与了正常子宫内膜间质细胞中第二个基因的前mRNA的反式剪接。一份报告发现JAZF1蛋白与孤儿核受体NR2C2共沉淀。类似于涉及2型糖尿病的全基因组关联研究发现，与2型糖尿病相关的JAZF1 SNP在物理上与与2型糖尿病相关的SNP通常在身高增加的人中发现，而内含子2中与内含子1 SNPs连锁不平衡区域之外的单独SNP与前列腺癌风险降低相关。在初步研究中，我们已经证明了与2型糖尿病相关的SNP导致成纤维细胞和扁桃体组织中JAZF1基因前mRNA的增加。似乎与这一发现一致，我们的研究还表明，缺乏功能JAZF1的基因敲除小鼠的基础血清胰岛素水平较低，对葡萄糖挑战有低血糖反应。在这项应用中提出的研究中，我们将进一步表征在淋巴细胞和各种人类组织中包含与2型糖尿病相关的SNP的JAZF1等位基因表达的变化。我们将在JAZF-/-小鼠身上进行高胰岛素-正常血糖和高血糖钳夹实验，以确定与野生型小鼠相比，已经检测到的对胰岛素和葡萄糖代谢的影响是否与胰岛素敏感性和/或胰岛β细胞胰岛素分泌的变化有关。我们还将确定JAZF1转基因的表达是否会改变培养细胞的胰岛素敏感性和/或胰岛素分泌。最后，我们将确定JAZF1结合的蛋白质以及JAZF1诱导的RNA水平的变化。综上所述，这些研究将极大地促进对JAZF1特别是SNP变异如何影响2型糖尿病和其他疾病易感性的理解。 公共卫生相关性：本申请中提议的研究涉及疾病遗传风险和体质特征的全基因组关联(WGA)研究；单核苷酸多态(SNP)与疾病风险变化相关的机制；疾病的多基因风险；2型糖尿病的遗传易感性；以及JAZF1基因在正常细胞和功能障碍细胞中的功能。

DESCRIPTION (provided by applicant): Studies involving surveys of single nucleotide polymorphisms (SNPs) throughout the entire human genome have recently detected an association of a SNP in the first exon of the JAZF1 gene and individuals with type 2 diabetes. The biologic basis of this association is unknown. Moreover, little is known about the function of this gene in general. Its protein product is present in most human cells and is located in both the cytoplasm and the nucleus. The 5' end of JAZF1 is part of a gene fusion present in endometrial stromal tumors, and pre-mRNA transcribed from the gene participates in trans-splicing with pre-mRNA of a second gene within normal endometrial stromal cells. One report has found that JAZF1 protein co-precipitates with an orphan nuclear receptor, NR2C2. Whole genome association studies similar to those involving type 2 diabetes have found that a JAZF1 SNP physically linked closely to that correlated with type 2 diabetes is commonly found in people of increased height and a separate SNP in intron 2, outside the area of linkage disequilibrium with the intron 1 SNPs, is associated with decreased risk of prostate cancer. In preliminary studies, we have shown that the SNP associated with type 2 diabetes leads to increased pre-mRNA from the JAZF1 gene in fibroblasts and tonsil tissue. Seemingly consistent with that finding, our studies have also shown that knockout mice lacking functional JAZF1 have low basal serum insulin levels and a hypoglycemic response to glucose challenge. In research proposed in this application, we will further characterize in lymphocytes and various human tissues the altered expression of JAZF1 alleles containing the SNP associated with type 2 diabetes. We will conduct hyperinsulinemic-euglycemic and hyperglycemic clamp experiments on the JAZF-/- mice to determine if the effect already detected on insulin and glucose metabolism is related to changes in insulin sensitivity and/or insulin secretion from pancreatic beta cells, compared to wild type mice. We will also determine whether expression of JAZF1 transgenes inserted into cultured cells alters insulin sensitivity and/or insulin secretion. Finally, we will identify proteins to which JAZF1 binds and changes in levels of RNA induced by JAZF1. Taken together, these studies will greatly advance understanding of how JAZF1 in particular and SNP variants in general may influence susceptibility to type 2 diabetes and other diseases. PUBLIC HEALTH RELEVANCE: The research proposed in this application is relevant to whole genome association (WGA) studies of inherited risk of diseases and constitutional traits; mechanisms by which single nucleotide polymorphisms (SNP) are associated with altered risk of disease; polygenic risks of disease; genetic susceptibility to type 2 diabetes; and the function of the JAZF1 gene in normal and dysfunctional cells.