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.

我们一直在跟进PIMA印第安人先前全基因组关联（GWA）研究（100K）的关联信号。迄今为止，在几个基因组区域中，基因分型进行了4035个SNP，用于精细映射。我们还正在测试最佳SNP的人群级别的重要性，迄今为止，在3500个全雄力PIMA印第安人的基于人群的样本中，基因分型超过1703个SNP。在强大的心脏研究中，正在进一步测试选定的SNP，并在另外4100名PIMA印第安人以及3000名美洲原住民中进行了复制。我们已经确定了与糖尿病密切相关的NELL-1基因附近的变体，我们目前正在尝试建立功能变体。此外，我们已经确定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MBL2基因中映射的GWA鉴定的另一个SNP，该SNP编码了甘露糖结合凝集素蛋白。该蛋白质是先天免疫系统中的关键参与者，最近被发现在1型糖尿病和妊娠糖尿病的胰岛素抵抗和发育中发挥作用。已显示出影响血清MBL2蛋白水平的变体与两种独立的皮马印第安人和阿米什人种群中的2型糖尿病有关。