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性（SNP）调查的研究最近发现JAZF 1基因第一外显子中的SNP与2型糖尿病个体相关。这种关联的生物学基础尚不清楚。此外，人们对这个基因的功能知之甚少。它的蛋白质产物存在于大多数人类细胞中，位于细胞质和细胞核中。JAZF 1的5'末端是子宫内膜间质肿瘤中存在的基因融合体的一部分，并且从该基因转录的前体mRNA参与与正常子宫内膜间质细胞内的第二基因的前体mRNA的反式剪接。一份报告发现JAZF 1蛋白与孤儿核受体NR 2C 2共沉淀。与涉及2型糖尿病的研究类似的全基因组关联研究发现，与2型糖尿病相关的JAZF 1 SNP在物理上紧密连锁，通常见于身高增加的人群，内含子2中的一个单独SNP，在与内含子1 SNP连锁不平衡的区域之外，与前列腺癌风险降低相关。在初步研究中，我们已经表明，与2型糖尿病相关的SNP导致成纤维细胞和扁桃体组织中JAZF 1基因的前mRNA增加。与这一发现似乎一致的是，我们的研究还表明，缺乏功能性JAZF 1的敲除小鼠具有低基础血清胰岛素水平和对葡萄糖挑战的低血糖反应。在本申请提出的研究中，我们将进一步表征淋巴细胞和各种人体组织中含有与2型糖尿病相关的SNP的JAZF 1等位基因的表达改变。我们将对JAZF-/-小鼠进行高胰岛素-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/或胰腺β细胞胰岛素分泌的变化有关。我们还将确定插入培养细胞的JAZF 1转基因的表达是否改变胰岛素敏感性和/或胰岛素分泌。最后，我们将确定JAZF 1结合的蛋白质和JAZF 1诱导的RNA水平的变化。总之，这些研究将极大地促进对JAZF 1和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：本申请中提出的研究与疾病遗传风险和体质特征的全基因组关联（WGA）研究相关;单核苷酸多态性（SNP）与疾病风险改变相关的机制;疾病的多基因风险; 2型糖尿病的遗传易感性;以及JAZF 1基因在正常和功能失调细胞中的功能。

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.