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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。大量证据支持在染色体1q21-Q23上存在几种易感基因（T2DM）。在几个高加索人群中，已重复了肝丙酮酸激酶基因（PKLR）与T2DM的变体的关联，但缔合区域较广，包括至少6个表达基因。该提案将检验以下假设：该区域中的非编码变体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中肝葡萄糖的产生增加。提出了一种多方面的方法，该方法将首先使用单核苷酸多态性定义高加索和非裔美国人受试者的关联区域（AIM 1）。在该区域内，将筛选所有编码，保守和推定的监管区域的变化，以了解24名高加索人和24个非裔美国人个体的差异。将寻求重复和重排改变基因拷贝数的证据（AIM 2）。 AIM 3将测试在皮下脂肪，肌肉和永生的淋巴细胞中该区域的所有可及其基因的基因型表达水平差异，并将在发现转录序列中常见变体的等位基因表达中测试差异。 AIM 4将测试每个单倍型纯合子的10个个体，以确定胰岛素的分泌，电子糖夹的胰岛素敏感性和肝葡萄糖产生。将获得脂肪和肌肉，以将表型与该区域基因的表达谱相关。这些研究可能会识别导致T2DM的特定核苷酸变体，或者可以识别增加该区域易感性的途径和基因。