A genotype first approach to studying diabetes

研究糖尿病的基因型优先方法

• 批准号: 10388618
• 负责人: Lauren Stalbow
• 金额: $ 4.59万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2025-09-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10388618
• 关键词: Address; Age; American; Caring; Clinical; Development; Diabetes Mellitus; Diabetes prevention; Diagnosis; Diagnostic; Disease; Disease Management; Epidemic; Ethnic group; European; Family; Gene Mutation; Genes; Genetic Variation; Genotype; Goals; Health; Individual; Insulin-Dependent Diabetes Mellitus; Knowledge; Medical Care Costs; Medicine; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Penetrance; Phenotype; Population; Prevalence; Research; Risk; Structure of beta Cell of islet; Therapeutic; Variant; base; biobank; diabetes mellitus genetics; diabetes risk; functional disability; improved; individualized prevention; multi-ethnic; novel; phenome; population based; societal costs; trait

PROJECT SUMMARY Ten percent of Americans suffer from diabetes, and in the next twenty years this number is projected to rise alongside disease related medical and societal costs. With the rise in prevalence of diabetes, early and precise diagnosis of diabetes subtypes are crucial for correct treatment and management of the disease. Maturity Onset Diabetes of the Young (MODY) is a rare familial monogenic form of diabetes that is caused by mutations in genes that are involved in the development and function of the pancreatic beta cell, and is often misdiagnosed as other diabetes subtypes. Mutations in the MODY genes not only cause MODY; mutations with less severe functional impairment have been shown to associate with type 2 diabetes (T2D) risk. Rare mutations have been difficult to study in a population-based setting because of how infrequently they present in the population. Historically, MODY has been studied in small family-based settings, likely biasing penetrance estimates and missing the complete phenotypic picture of the disease. The majority of MODY gene research has been done in European ancestry individuals, making it more difficult for non-European ancestry groups to access genetically-informed medicine. With the availability of large-scale and diverse biobanks, such as the Mount Sinai BioMe biobank and the UK Biobank (UKBB), it is now possible to study MODY gene mutations in a multi-ancestry population setting and assess their impact on MODY, T2D and related traits. To address the current knowledge gaps, we propose the following aims: Aim 1- To assess and interrogate known and novel MODY-causing mutations in individuals of diverse ancestry of the BioMe Biobank and UKBB. We will do this by examining the penetrance and expressivity of diabetes in MODY-causing mutations, broadening the clinical spectrum of MODY-causing mutations by applying phenome-wide association studies and identifying previously unknown MODY-causing mutations. We hypothesize that estimates of penetrance of known MODY-causing mutations will be more accurate than family based findings, the clinical spectrum of phenotypic associations for known MODY-causing mutations will be broadened, and we will discover novel MODY-causing mutations. We further aim to use the population-based biobanks to study the interplay between rare and common genetic variation and the association to T2D and related traits. We propose: Aim 2- To examine how individuals’ risk of T2D is influenced by polygenic risk of T2D and mutations in MODY genes in BioMe and the UKBB. We will examine the impact of rare functionally damaging MODY gene mutations on T2D among individuals with low and high polygenic risk of T2D and glycemic traits. We hypothesize that carrying a damaging mutation will exacerbate the risk of T2D conferred by a polygenic burden. These steps toward understanding the impact of rare MODY gene mutations will facilitate our long-term objective to better understand the genetics of diabetes, and implement precision prevention, diagnostics and therapeutics to diabetes medicine.

项目摘要 百分之十的美国人患有糖尿病，在接下来的二十年中，这个数字预计 与疾病相关的医疗和社会成本并肩上升。随着糖尿病患病率的升高，早期和 糖尿病亚型的精确诊断对于疾病的正确治疗和管理至关重要。 年轻人（Mody）的成熟糖尿病是一种罕见的家族性糖尿病形式，是由糖尿病引起的 涉及胰腺β细胞发展和功能的基因突变，通常是 误诊为其他糖尿病亚型。 Mody基因中的突变不仅引起Mody；突变 由于功能障碍较少，已显示与2型糖尿病（T2D）风险相关。稀有的 在基于人群的环境中很难研究突变，因为它们很少存在 人口。从历史上看，Mody一直在基于家庭的小型环境中研究，可能会偏向于货币 估计和缺少疾病的完整表型图。大多数Mody Gene研究 在欧洲血统的个人中完成了 进入遗传信息。随着大规模和潜水生物库的可用性，例如 西奈山生物群生物库和英国生物库（UKBB），现在可以研究Mody Gene突变 多委托人的种群设置并评估其对Mody，T2D和相关特征的影响。 为了解决当前知识差距，我们提出以下目的：目标1-评估和 在生物群体的多样性祖先中询问已知和新颖的Mody引起的突变 生物银行和UKBB。我们将通过检查糖尿病的外观和表现力来做到这一点 引起Mody的突变，通过应用范围扩大了Mody引起的突变的临床光谱 整个现象的关联研究并鉴定以前未知的Mody引起的突变。我们 假设对已知Mody引起突变的渗透率的估计比家族更准确 基于发现的结果，已知致死突变的表型关联的临床光谱将是 扩展了，我们将发现新型的Mody引起的突变。我们进一步使用基于人群的 生物库研究罕见和常见遗传变异以及与T2D的关联之间的相互作用 相关特征。我们建议：目标2-研究个人对T2D的风险如何受多基因风险的影响 Biome和UKBB中Mody基因的T2D和突变。我们将研究罕见的影响 在低多基因风险的个体中，在功能上损害了T2D的Mody基因突变 T2D和血糖特征。我们假设携带破坏突变会加剧T2D的风险 由多基因伯宁（多基因伯宁）授予。这些步骤了解稀有Mody基因突变的影响 将促进我们的长期目标，以更好地了解糖尿病的遗传学并实施精度 预防，诊断和治疗糖尿病医学。