Discovery of Functional Variants in Type 2 Diabetes Genes in Mexican Americans

墨西哥裔美国人 2 型糖尿病基因功能变异的发现

• 批准号: 7791521
• 负责人: HANNA E ABBOUD
• 金额: $ 51.15万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791521
• 关键词: Adult; Adult Children; Affect; Bayesian Method; Beta Cell; Birth Weight; Body mass index; Candidate Disease Gene; Cell physiology; Child; DNA; DNA Resequencing; Data; Developed Countries; Developing Countries; Drug Delivery Systems; Epidemic; European; Extended Family; Family; Family Study; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Techniques; Genomics; Genotype; Individual; Insulin Resistance; Intervention; Knowledge; Linkage Disequilibrium; Lymphocyte; Measures; Mexican Americans; Minority; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Participant; Play; Population; Population Heterogeneity; Prediabetes syndrome; Predisposition; Prevalence; Probability; Proxy; Risk; Role; Sample Size; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Speed; Susceptibility Gene; TCF7L2 gene; Techniques; United States; Variant; base; cost; design; genetic association; genetic variant; genome wide association study; health disparity; improved; interest; member; next generation; non-diabetic; novel; public health relevance; trait; waist circumference

DESCRIPTION (provided by applicant): The prevalence of type 2 diabetes (T2DM) has been increasing at epidemic proportions worldwide including significantly increased rates among United States (US) minority populations such as Mexican Americans. To date, knowledge about the genetic determinants of T2DM is very limited. However, recent genome-wide association studies (GWASs) of T2DM in populations of European ancestry have localized 19 putative genomic regions that may harbor relevant susceptibility loci. These initial findings reflect association signals related to common variants. The identity of the underlying causal genes and their functional variants still remain unknown. Efforts to replicate the original association findings in ethnically diverse populations have not been universally successful, perhaps due to issues such as allele frequency and linkage disequilibrium (LD) differences. Therefore, an exhaustive resequencing-based search of the genomic regions surrounding these original genetic signals in ethnically diverse populations is required to help identify the underlying causal genes and their likely functional variants. In the proposed project, we will attempt to identify causal variants influencing T2DM based on existing localizations obtained from GWA studies using data/samples from five Mexican American family studies in San Antonio (N = 5,638). To fulfill our objective, we will identify all sequence variants in an approximately 250 kb region around the single nucleotide polymorphism (SNP) of interest by deep resequencing of the selected 16 T2DM candidate gene regions identified from GWASs (Aim 1). Using a highly efficient family-based design, we will then identify the most likely functional variants influencing risk of T2DM in 1,000 effectively sequenced individuals using a novel statistical prioritization method, Bayesian quantitative trait nucleotide (BQTN). The most strongly associated 50 SNPs from Aim 2 will then be typed in a sample of 5,030 adults to confirm their association with T2DM (Aim 3). In addition, we will examine whether the variants found to be significant in adults affect T2DM related traits in ~600 non-diabetic children. To carry out the study, advanced next generation sequencing techniques will be combined with unique computationally intensive statistical genetic techniques to predict those variants most likely to play causal roles in T2DM risk. RELEVANCE: Identification of T2DM susceptibility genes in Mexican Americans will have major public health relevance in the US and in developed and developing countries. Identification of genes causally involved in T2DM risk may dramatically speed the quest for novel drug targets and improved pharmacologic interventions. Genetic findings in Mexican Americans may help explain health disparities among US populations.

描述（由申请人提供）：在全球流行病上，2型糖尿病（T2DM）的患病率一直在增加，包括美国（美国）少数民族（例如墨西哥裔美国人）的发生率显着提高。迄今为止，有关T2DM遗传决定因素的知识非常有限。但是，T2DM在欧洲血统人群中的最新基因组关联研究（GWASS）将19个可能具有相关易感位点的假定基因组区域定位。这些初始发现反映了与常见变体有关的关联信号。基本因果基因及其功能变体的身份仍然未知。复制种族多元化种群中最初的关联发现的努力并没有普遍成功，这可能是由于等位基因频率和连锁不平衡（LD）差异等问题所致。因此，需要基于详尽的重新等式搜索围绕种族多样性种群中这些原始遗传信号的基因组区域，以帮助识别基本的因果基因及其可能的功能变异。在拟议的项目中，我们将尝试根据使用来自GWA研究获得的现有本地化来确定影响T2DM的因果变异，并使用来自圣安东尼奥的五个墨西哥裔美国家庭研究的数据/样本（n = 5,638）。为了实现我们的目标，我们将通过对所选16个T2DM候选基因区域的深度重新取代从GWASS中确定的单个核苷酸多态性（SNP）围绕单个核苷酸多态性（SNP）确定所有序列变体（AIM 1）。然后，我们将使用高效的家庭设计，并使用一种新型的统计优先级化方法贝叶斯定量性状核苷酸（BQTN）来确定影响1,000个有效测序个体T2DM风险的最可能的功能变体。然后，来自AIM 2的最密切相关的50个SNP将在5,030名成年人的样本中键入，以确认他们与T2DM的关联（AIM 3）。此外，我们将研究发现成人中发现的变体是否影响约600名非糖尿病儿童的T2DM相关性状。为了进行研究，先进的下一代测序技术将与独特的计算密集统计遗传技术相结合，以预测最有可能在T2DM风险中扮演因果关系的变体。 相关性：识别墨西哥裔美国人T2DM易感基因的识别，将在美国以及发达国家和发展中国家具有主要的公共卫生相关性。鉴定与T2DM风险的因果关系的鉴定可能会大大加快对新型药物靶标的追求和改善的药理干预措施。墨西哥裔美国人的遗传发现可能有助于解释美国人群中的健康差异。