MOLECULAR CHARACTERIZATION OF PC-1 IN TYPE 2 DIABETES IN MEXICAN-AMERICANS

墨西哥裔美国人 2 型糖尿病中 PC-1 的分子特征

• 批准号: 7378143
• 负责人: CHRISTOPHER P JENKINSON
• 金额: $ 0.13万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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/7378143
• 关键词: MOLECULAR; CHARACTERIZATION; PC; TYPE; DIABETES

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. OBJECTIVE: The primary objective of this study is to test the hypothesis that the PC-1 gene is involved in the insulin resistance, and therefore contributes to the development of type 2 diabetes mellitus (T2DM) in Mexican Americans. If an association is observed between polymorphisms within, or near, the PC-1 gene and insulin resistance, and nearby genes can be excluded, further functional studies will be pursued. These include examination of PC-1 mRNA stability and expression levels, and direct measurement of insulin receptor tyrosine phosphorylation levels in CHO/IR cells co-expressing the insulin receptor and PC-1 variants. RESEARCH PLAN AND METHODS: State-of-the-art methods will be used to quantitate insulin receptor tyrosine phosphorylation, thereby defining the insulin resistance phenotype at the molecular level. Single nucleotide polymorphisms (SNPs) will be identified by direct DNA sequencing of the PC-1 gene in individuals with normal (N=10) and impaired (N=10) skeletal muscle insulin receptor phosphorylation. High-throughput assays will be designed to screen SNPs with allele frequencies 10%. Selected SNPs will be screened within a larger population sample of Mexican Americans (N=1137) derived from the SAFADS and GENNID studies. SNP genotypes will be statistically analyzed for association with insulin receptor tyrosine phosphorylation, insulin resistance, and other T2DM phenotypes. Linkage data will be utilized in cutting-edge combined linkage/linkage disequilibrium analyses with these SNPs to detect functional variants, which may underlie the observed linkage peak. CLINICAL RELEVANCE: Mexican Americans represent approximately 52% of the San Antonio population. This population has an extremely high prevalence of T2DM, and an improved understanding of the underlying genetic mechanisms of T2DM, therefore, well serves the needs of this population. In this ethnic group insulin resistance is severe and is well established before the onset of overt diabetes. Functional studies have established that mutations within the PC-1 gene lead to impaired insulin signaling. These studies provide convincing evidence of a direct mechanism for PC-1 involvement in insulin resistance. The gene is located within a chromosomal region that has been genetically linked to insulin resistance in Mexican Americans in the San Antonio Family Diabetes Study (SAFADS). The linked region, on the long arm of chromosome 6, produced a logarithm of the odds (LOD) score of 5.8 for linkage with a bivariate insulin resistance/obesity phenotype (leptin + HOMA IR). This is one of the strongest genetic signals ever recorded for a common multifactorial disease. Within this highly significant region, PC-1 is the strongest positional candidate gene and highly likely to be an important susceptibility gene for insulin resistance/T2DM in this at-risk population.

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。目的：本研究的主要目的是检验PC-1基因参与胰岛素抵抗的假设，因此有助于墨西哥裔美国人2型糖尿病（T2 DM）的发展。如果在PC-1基因内或附近的多态性与胰岛素抵抗之间观察到关联，并且可以排除附近的基因，则将进行进一步的功能研究。这些包括检查PC-1 mRNA的稳定性和表达水平，以及在共表达胰岛素受体和PC-1变体的CHO/IR细胞中直接测量胰岛素受体酪氨酸磷酸化水平。 研究方法：将使用最先进的方法定量胰岛素受体酪氨酸磷酸化，从而在分子水平上定义胰岛素抵抗表型。将通过对骨骼肌胰岛素受体磷酸化正常（N=10）和受损（N=10）个体的PC-1基因进行直接DNA测序，鉴定单核苷酸多态性（SNP）。将设计高通量测定以筛选等位基因频率10%的SNP。将在来自SAFADS和GENNID研究的墨西哥裔美国人（N=1137）的较大人群样本中筛选选定的SNP。将统计分析SNP基因型与胰岛素受体酪氨酸磷酸化、胰岛素抵抗和其他T2 DM表型的相关性。连锁数据将用于这些SNP的尖端组合连锁/连锁不平衡分析，以检测可能构成观察到的连锁峰的功能变体。 临床相关性：墨西哥裔美国人约占圣安东尼奥人口的52%。这一人群的T2 DM患病率极高，因此，对T2 DM潜在遗传机制的了解更好地满足了这一人群的需求。在这个种族群体中，胰岛素抵抗是严重的，并且在明显的糖尿病发作之前就已经确立。功能研究已经确定PC-1基因内的突变导致胰岛素信号传导受损。这些研究为PC-1参与胰岛素抵抗的直接机制提供了令人信服的证据。在圣安东尼奥家庭糖尿病研究（SAFADS）中，该基因位于与墨西哥裔美国人的胰岛素抵抗有遗传联系的染色体区域内。在染色体6的长臂上的连锁区域产生了与双变量胰岛素抵抗/肥胖表型（瘦素+ HOMA IR）连锁的比值（LOD）分数的对数为5.8。这是有史以来记录的常见多因素疾病的最强遗传信号之一。在这个高度显着的区域内，PC-1是最强的位置候选基因，并且很可能是该高危人群中胰岛素抵抗/T2 DM的重要易感基因。