Follow-Up Studies of a Genome-Wide Association Analysis in Pima Indians

皮马印第安人全基因组关联分析的后续研究

• 批准号: 7734345
• 负责人: Leslie J Baier
• 金额: $ 59.05万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734345
• 关键词: Acute; Affect; Age; Age of Onset; Amish; Arizona; Body fat; Body mass index; Diabetes Mellitus; Disease; Euglycemic Clamping; Family; Follow-Up Studies; Genes; Genomics; Genotype; Gestational Diabetes; Glucose; Glucose Clamp; Heart; Immune system; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intravenous Bolus; Mannose Binding Lectin; Mannose-Binding Lectins; Maps; Measures; Metabolic Pathway; Native Americans; Non-Insulin-Dependent Diabetes Mellitus; Phase; Phenotype; Pima Indian; Play; Population; Prevalence; Proteins; Reporting; Resistance development; Role; Sampling; Serum; Siblings; Signal Transduction; Significance Level; Techniques; Testing; Variant; base; case control; design; diabetic; early onset; follow-up; genome wide association study; non-diabetic; response; trait

We have been following-up association signals from our prior genome-wide association (GWA) study (100k) in Pima Indians. To date, have genotyped more than 4035 SNPs for fine-mapping in several genomic regions. We are also testing the population-level significance of the best SNPs and, to date, have genotyped more than 1703 SNPs in a population-based sample of 3500 full-heritage Pima Indians. Selected SNPs are being further tested for replication in an additional 4100 Pima Indians as well as 3000 Native Americans from the Strong Heart study. We have identified variants near the NELL-1 gene that are strongly associated with diabetes and we are currently trying to establish the functional variant. In addition, we have identified variation within the A2BP1 gene that is highly associated with body mass index and we are currently trying to determine the metabolic pathway that is affected by this gene. Another SNP that was identified via the GWA mapped within the MBL2 gene that encodes the mannose-binding lectin protein. This protein is a key player in the innate immune system, and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes. Variants which have previosuly been shown to influence serum MBL2 protein levels were associated with type 2 diabetes in two independent groups of Pima Indians as well as an Amish population.

我们一直在追踪之前针对皮马印第安人的全基因组关联 (GWA) 研究 (100k) 的关联信号。迄今为止，我们已对超过 4035 个 SNP 进行了基因分型，以便在多个基因组区域进行精细定位。我们还在测试最佳 SNP 在人群水平上的显着性，迄今为止，我们已在 3500 名纯种皮马印第安人的人群样本中对超过 1703 个 SNP 进行了基因分型。选定的 SNP 正在另外 4100 名皮马印第安人和 3000 名来自 Strong Heart 研究的美洲原住民中进行进一步测试。我们已经鉴定出 NELL-1 基因附近与糖尿病密切相关的变异，目前我们正在尝试建立功能变异。此外，我们还发现了与体重指数高度相关的 A2BP1 基因内的变异，目前我们正在尝试确定受该基因影响的代谢途径。通过 GWA 鉴定的另一个 SNP 位于编码甘露糖结合凝集素蛋白的 MBL2 基因内。这种蛋白质是先天免疫系统的关键参与者，最近被发现在胰岛素抵抗以及 1 型糖尿病和妊娠糖尿病的发展中发挥着重要作用。先前已被证明影响血清 MBL2 蛋白水平的变异与两个独立的皮马印第安人和阿米什人群中的 2 型糖尿病相关。