CHARACTERIZATION OF TYPE 2 DIABETES SUSCEPTIBILITY ALLELES AT THE PKLR LOCUS

PKLR 位点 2 型糖尿病易感性等位基因的特征

• 批准号: 7377691
• 负责人: Steven C Elbein
• 金额: $ 0.96万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377691
• 关键词: CHARACTERIZATION; TYPE; DIABETES; SUSCEPTIBILITY; ALLELES

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Considerable evidence supports the existence of several susceptibility genes for type 2 diabetes (T2DM) on chromosome 1q21-q23. Association of variants near the liver pyruvate kinase gene (PKLR) with T2DM has been replicated in several Caucasian populations, but the region of association is broad and includes at least 6 expressed genes. This proposal will test the hypothesis that noncoding variants in this region alter expression of one or more genes and result in increased hepatic glucose production among individuals carrying the susceptible haplotype. A multifaceted approach is proposed, that will first define the region of association in both Caucasian and African American subjects using single nucleotide polymorphisms (Aim 1). Within this region, variation in all coding, conserved, and putative regulatory regions will be screened for variation in 24 Caucasian and 24 African American individuals. Evidence for duplications and rearrangements altering gene copy number will be sought (Aim 2). Aim 3 will test for differences in expression levels by genotype for all amenable genes in this region in subcutaneous fat, muscle, and immortalized lymphocytes, and will test for differences in allelic expression where common variants in transcribed sequences are found. Aim 4 will test 10 individuals homozygous for each haplotype to determine insulin secretion, insulin sensitivity by euglycemic clamp, and hepatic glucose production. Fat and muscle will be obtained to correlate phenotype with expression profiles of genes in this region. These studies may identify the specific nucleotide variant leading to T2DM, or alternatively will identify the pathway and genes that increase susceptibility in this region.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。大量证据支持染色体1 q21-q23上存在多个2型糖尿病（T2 DM）易感基因。肝脏丙酮酸激酶基因（PKLR）附近的变异体与T2 DM的关联已在几个高加索人群中重复，但关联区域很广，包括至少6个表达基因。该提议将检验这一假设，即该区域的非编码变异改变了一个或多个基因的表达，并导致携带易感单倍型的个体的肝葡萄糖产量增加。提出了一种多方面的方法，首先使用单核苷酸多态性（目的1）定义高加索人和非洲裔美国人受试者的关联区域。在该区域内，将在24名高加索人和24名非裔美国人个体中筛选所有编码区、保守区和推定调控区的变异。将寻找重复和重排改变基因拷贝数的证据（目标2）。目标3将测试皮下脂肪、肌肉和永生化淋巴细胞中该区域所有顺从基因的基因型表达水平差异，并测试转录序列中常见变异的等位基因表达差异，目标4将测试每个单倍型的10个纯合个体，以确定胰岛素分泌、正葡萄糖钳夹胰岛素敏感性和肝葡萄糖产生。将获得脂肪和肌肉以将表型与该区域中基因的表达谱相关联。这些研究可以确定导致T2 DM的特定核苷酸变异，或者确定增加该区域易感性的途径和基因。