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

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

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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（占人口的约10％）患有糖尿病，其中90-95％是2型糖尿病（T2D）。 T2D是美国健康并发症的主要原因，少数患有糖尿病的种群更有可能经历微血管并发症，大血管疾病，随后的死亡，即使进入白人疾病照顾是可比的。高血糖器官损伤的病理生理学，以及为什么有些患者相对幸免，在很大程度上未知。侵袭性血糖控制已知减少糖尿病并发症的频率，尤其是微血管，但是很少患者能够达到推荐的血糖靶标。遗传变异已知导致T2D并发症的风险。但是，糖尿病的遗传关联研究并发症直到最近才开始揭示特定的基因和途径提高敏感性。尽管这些发现显示了这种方法的承诺，但有一个迫切需要更好地了解高血糖导致器官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见解通过使用大规模样本量，考虑多效性，环境调制和遗传亚型。提出了以下特定目的来检验此假设1）基因组在五个种族中，在185K受试者中对糖尿病并发症的多效性分析 - 种族群体； 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制对遗传风险T2D并发症的作用，最高130万有和没有T2D的受试者； 3）糖尿病患者的遗传风险特征和因果推断识别因果风险因素并解散因素之间的关系的并发症 T2D及其并发症。这项工作有可能阐明糖尿病并发症，并提供对生物学和知识的见解，以指导开发潜在的临床预测因子，预防策略和指导的发展新疗法。