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

超过3400万美国人(约占总人口的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，少数人 糖尿病患者更容易出现微血管并发症， 大血管疾病，以及随后的死亡甚至比他们的白人同行更接近 关爱是可以比拟的。高血糖器官损害的病理生理学，以及为什么一些 患者相对幸免于难，但仍在很大程度上未知。积极的血糖控制是已知的 然而，为了减少糖尿病并发症的发生率，特别是微血管并发症，很少 患者能够达到推荐的血糖目标。已知的遗传变异 增加了T2D并发症的风险。然而，糖尿病的遗传相关性研究 并发症直到最近才开始揭示特定的基因和通路 以增加敏感度。虽然这些发现显示了这种方法的前景，但也存在一个 迫切需要更好地了解高血糖导致器官损伤的机制 损害和增加糖尿病并发症的基因发现。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洞察力 通过使用大规模样本量，考虑了多效性、环境调制和 基因亚型。提出了以下具体目标来检验这一假说1)基因组 并对185K受试者进行了跨五个种族的T2D糖尿病并发症的多效性分析。 2)糖尿病并发症的基因x环境(GxE)交互作用分析 考虑环境调节对高达1.3米的遗传风险T2D并发症的作用 患有和不患有T2D的受试者；以及3)糖尿病患者的遗传风险特征和因果推断 找出并发症的病因危险因素，理清各因素之间的关系 T2D及其并发症。这项工作有可能阐明 并提供对生物学的见解和至关重要的知识，以指导 制定潜在的临床预测指标、预防和指导发展的策略 新疗法。

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.