Genomic, gene-environment and casual inference studies in diabetic complications

糖尿病并发症的基因组、基因环境和随意推理研究

基本信息

批准号：
10639507
负责人：
RANY SALEM
金额：
$ 57.41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639507
关键词：
Adult Affect Albuminuria American Amputation Biological Biology Blindness Blood Glucose Blood Vessels Cessation of life Classification Complex Complications of Diabetes Mellitus Coronary heart disease Data Data Analyses Development Diabetes Mellitus Disease End stage renal failure Environment Ethnic Population Frequencies Functional disorder Genes Genetic Genetic Predisposition to Disease Genetic Risk Genome Genomics Goals Health Health Services Accessibility Healthcare Heritability Heterogeneity Hyperglycemia Individual Inherited Kidney Diseases Knowledge Mediation Microvascular Dysfunction Minority Groups Neuropathy Non-Insulin-Dependent Diabetes Mellitus Organ Pathway interactions Patient Selection Patients Peripheral Vascular Diseases Phenotype Population Predisposition Prevention Prevention strategy Prevention therapy Productivity Recommendation Retinal Diseases Risk Risk Factors Risk Management Role Sample Size Smoking Smoking Status Stroke Testing Variant Work biobank clinical predictors comorbidity cost diabetes management experience gene discovery gene environment interaction genetic analysis genetic association genome-wide genomic locus glycemic control improved insight macrovascular disease new therapeutic target non-alcoholic fatty liver disease novel novel therapeutics pleiotropism precision medicine racial population rare variant risk sharing risk stratification risk variant sex

项目摘要

Over 34 million Americans (~10% of population) have diabetes, 90-95% of which is type 2 diabetes (T2D). T2D is a leading cause of health complications in the US, and minority populations with diabetes are more likely to experience microvascular complications, macrovascular disease, and subsequent death than their White counterparts even when access to care is comparable. The pathophysiology of hyperglycemic organ damage, and why some patients are relatively spared, remains largely unknown. Aggressive glycemic control is known to decrease the frequency of diabetic complications, particularly microvascular, however, few patients are able reach recommended glycemic targets. Inherited variation is known to contribute to the risk of T2D complications. However, genetic associations studies of diabetic complications have only recently begun to reveal the specific genes and pathways responsible for increased susceptibility. While these findings show the promise of this approach, there is an urgent need to better understand the mechanisms by which hyperglycemia leads to organ damage and increase genetic discoveries in diabetic complications. To achieve this goal, we hypothesize that genetics can further enhance the biological insights into diabetic complications by using large-scale sample size, consideration of pleiotropy, environmental modulation and genetic subtyping. The following Specific Aims are proposed to test this hypothesis 1) Genomic and pleiotropy analyses of diabetic complications in 185K subjects with T2D across five racial- ethnic groups; 2) Gene x environment (GxE) interaction analyses of diabetic complications to consider the role of environmental modulation on genetic risk T2D complications in up to 1.3M subjects with and without T2D; and 3) genetic risk profiles and causal inference in diabetic complications to identify causal risk factors and disentangle the relationship between the factors and T2D and its complications. This work has the potential to elucidate the mechanisms of diabetic complications and provide insights into biology and knowledge critical to guide the development of potential clinical predictors, strategies for prevention and guide development of new therapies.

超过 3400 万美国人（约占人口的 10%）患有糖尿病，其中 90-95% 为 2 型糖尿病（T2D）。 T2D 是美国健康并发症的主要原因，少数人糖尿病患者更容易出现微血管并发症，即使在访问时，大血管疾病和随后的死亡也比白人同行高照顾是可比的。高血糖器官损害的病理生理学，以及为什么有些患者相对幸存，但仍知之甚少。积极的血糖控制是众所周知的降低糖尿病并发症的发生率，特别是微血管并发症，然而，很少有患者能够达到推荐的血糖目标。已知遗传变异增加 T2D 并发症的风险。然而，糖尿病的遗传关联研究直到最近才开始揭示并发症的具体基因和途径以增加敏感性。虽然这些发现显示了这种方法的前景，但有一个迫切需要更好地了解高血糖导致器官衰竭的机制损害并增加糖尿病并发症的遗传发现。为了实现这一目标，我们假设遗传学可以进一步增强对糖尿病并发症的生物学认识通过使用大规模样本量、考虑多效性、环境调节和遗传亚型。提出以下具体目标来检验这一假设 1) 基因组对 5 个种族的 185,000 名 T2D 受试者的糖尿病并发症进行多效性分析族裔群体； 2）糖尿病并发症的基因x环境（GxE）相互作用分析考虑环境调节对高达 130 万例 T2D 并发症遗传风险的影响患有和不患有 T2D 的受试者； 3) 糖尿病的遗传风险概况和因果推断并发症以确定因果危险因素并理清因素之间的关系 T2D 及其并发症。这项工作有可能阐明其机制糖尿病并发症，并提供对指导糖尿病至关重要的生物学和知识的见解开发潜在的临床预测因子、预防策略并指导开发新疗法。