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

• 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
• 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

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 糖尿病（T2 D）。T2 D是美国健康并发症的主要原因，少数 患有糖尿病的人群更可能经历微血管并发症， 大血管疾病，并随后死亡比他们的白色同行，即使当访问 关怀是可比的。高血糖器官损伤的病理生理学，以及为什么一些 患者相对较少，仍然基本未知。积极的血糖控制是众所周知的 减少糖尿病并发症的频率，特别是微血管，然而，很少 患者能够达到推荐的血糖目标。已知遗传变异 增加了T2 D并发症的风险。然而，糖尿病患者的遗传相关研究 直到最近才开始揭示出引起这些并发症的特定基因和途径 增加易感性。虽然这些发现显示了这种方法的前景，但还有一个问题 迫切需要更好地了解高血糖导致器官损害的机制， 损害和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见解 通过使用大规模样本容量，考虑多效性，环境调制和 基因分型提出以下具体目标来检验这一假设1）基因组 在5个种族中，对185 K例T2 D受试者的糖尿病并发症进行了多效性分析。 2）糖尿病并发症的基因x环境（GxE）相互作用分析， 考虑环境调节对遗传风险T2 D并发症的作用， 患有和不患有T2 D的受试者;以及3）糖尿病患者的遗传风险特征和因果推断 并发症，以确定因果风险因素，并理清因素之间的关系 2型糖尿病及其并发症这项工作有可能阐明的机制， 糖尿病并发症，并提供生物学和知识的见解，关键是指导 开发潜在的临床预测因子、预防策略，并指导 新疗法