Leveraging electronic medical records to perform large-scale diabetes pharmacogenomics among ancestrally diverse patient populations

摘要 糖尿病是现代的祸害，影响全世界越来越多的人， 包括目前的2600万美国人。此外，2型糖尿病（T2 D） 历史上处于不利地位的美国少数民族群体，这一点可以从更高的疾病发病率和更多的 非裔美国人的严重并发症。虽然有多种治疗类别的 作为治疗T2 D的口服药物，二甲双胍目前被推荐为一线治疗。 二甲双胍通过减少肝脏新生血管生成，改善骨骼肌胰岛素水平， 敏感性和限制肠道葡萄糖摄取。它也被证明是一种有效的治疗方法， 预防糖尿病。尽管它是世界上最常用的处方药之一， 已知二甲双胍介导其作用的生物学机制。这些知识将 具有治疗价值，以更好地理解和预测治疗反应。推而广之， 已知二甲双胍在非裔美国人中的活性，因为很少有研究包括 大量非欧洲人口。这个应用程序将有助于纠正现有的知识 通过研究大量不同的T2 D患者人群，具体而言，我们将利用电子 用于大规模糖尿病药物基因组学的病历（EMR）数据。这些数据的优势在于 能够说明药物使用和药物暴露随时间的变化;提供大量的 个体进行组合和人群组特异性分析;并评估临床终点， 回顾性和前瞻性。在本申请中，我们提出以下研究目的：1）评估 二甲双胍治疗应答是否存在自我报告的人种-种族和遗传差异 2）使用新的，基于基因的关联方法来确定共享和人口群体 影响二甲双胍对血液流变学作用的特定遗传变异（即，HbA 1c水平）;以及3） 在一个单独的患者组中复制我们的发现，并包括额外的探索性分析，以评估 所鉴定的遗传变异是否影响糖尿病相关的微血管事件，大血管事件， 和药物不良反应。通过这项研究获得的知识将直接解决健康的目标 人民2020 -“实现健康公平，消除差距，提高所有群体的健康水平”。

ABSTRACT Diabetes mellitus is a modern day scourge, affecting an ever increasing proportion of individuals worldwide, including 26 million Americans currently. Moreover, type-2 diabetes (T2D) disproportionately affects historically disadvantaged U.S. minority groups, as evidenced by the much higher rates of disease and more severe complications among African American individuals. Although there are multiple therapeutic classes of oral medication available for treating T2D, metformin is currently recommended as the first-line therapy. Metformin lowers blood glucose levels by reducing hepatic gluconeogenesis, improving skeletal muscle insulin sensitivity, and limiting intestinal glucose uptake. It has also been shown to be an effective therapy for preventing incident diabetes. Despite being one of the most frequently prescribed drugs worldwide, very little is known about the biologic mechanism(s) through which metformin mediates its effect. This knowledge would be of value therapeutically to better understand and predict treatment response. By extension, even less is known about the activity of metformin among African American individuals, as few studies have included substantial numbers of non-European population groups. This application will help rectify existing knowledge gaps by studying a large and diverse patient population with T2D. Specifically, we will utilize electronic medical record (EMR) data for large-scale diabetes pharmacogenomics. These data have the advantage of being able to account for medication use and drug exposure over time; to provide substantial numbers of individuals for combined and population group specific analyses; and to assess clinical end-points both retrospectively and prospectively. In this application, we propose the following study aims: 1) To assess whether there are differences in metformin treatment response by self-reported race-ethnicity and genetic ancestry; 2) To use novel, gene-based association approaches to identify both shared and population group specific genetic variants influencing metformin's effect on blood glycemia (i.e., HbA1c levels); and 3) To replicate our findings in a separate group of patients and to include additional exploratory analyses to assess whether the identified genetic variants influence diabetes-related microvascular events, macrovascular events, and adverse drug reactions. The knowledge gained through this study will directly address the goals of Health People 2020 – “achieve health equity, eliminate disparities, and improve the health of all groups.”