Genetics of glucocorticoid-induced hyperglycemia

摘要 糖皮质激素是一种常见的药物，用于治疗多种炎症性和自身免疫性疾病。 它们的临床应用受到多种副作用的限制，最常见的是高血糖。高血糖症 已被证明对疾病进展、发病率和死亡率有负面影响。约50%的 服用糖皮质激素的患者会出现高血糖，这表明这种疾病具有异质性。进一步 了解谁会患上高血糖可能有助于预防和早期治疗此类疾病 个人。 虽然糖皮质激素引起的高血糖的分子机制还没有完全确定， 有证据表明，这种疾病的发病机制反映了2型糖尿病的发病机制。 (T2D)。糖皮质激素诱导的高血糖也被认为是由胰岛素抵抗增加引起的。 由于胰岛β细胞功能下降。我们的初步数据表明，全基因组关联研究(GWAS) 糖尿病和胰岛素相关性状的糖皮质激素基因丰富，进一步证实了这种重叠 在这两种疾病之间。因此，我们假设糖尿病和胰岛素的遗传风险分数- 相关性状可用于预测糖皮质激素的血糖反应。 在具体目标1中，我们将通过研究巩固糖皮质激素基因与糖尿病的关系 糖皮质激素基因中的T2D遗传变异是如何发现的。具体地说，我们将对 评估受试者之间是否存在糖皮质激素基因序列差异的糖皮质激素相关基因 无论有没有糖尿病。在具体目标2中，我们将使用生物库资源来识别具有和 无糖皮质激素引起的高血糖。然后，我们将构建糖尿病的遗传风险评分(GRS) 和胰岛素相关的表型。我们将确定这些GR和 糖皮质激素性高血糖的发生。然后，我们将利用找到的新信息 目的1建立T2D相关糖皮质激素相关基因的GRS。我们将利用这部小说的GRS来 比较有无糖皮质激素性高血糖的受试者。因此，我们将研究这两种情况 糖皮质激素相关基因影响糖尿病风险，如果糖尿病相关基因影响糖皮质激素风险- 诱发高血糖。 这些目标反映了一项精心计划的培训计划，旨在推动 申请人。博德研究所和麻省理工学院人类基因研究中心的资源 糖尿病遗传学领域的领先专家何塞·弗洛雷斯的指导将允许尖端基因组 发现和先进的分析方法将被应用于研究基因变异 糖皮质激素引起的高血糖。

Abstract Glucocorticoids are a common medication used to treat a myriad of inflammatory and autoimmune diseases. Their clinical use is limited by multiple side effects, the most common being hyperglycemia. Hyperglycemia has been shown to negatively impact disease progression, morbidity and mortality. Approximately 50% of patients taking glucocorticoids develop hyperglycemia, suggesting heterogeneity in this disease. Further understanding of who develops hyperglycemia may allow for prevention and earlier treatment such individuals. While the molecular mechanisms underlying glucocorticoid-induced hyperglycemia are not completely defined, there is evidence that the mechanisms of this disease mirror the mechanisms underlying type 2 diabetes (T2D). Glucocorticoid-induced hyperglycemia is thought to be caused by increased insulin resistance as well as decreased beta cell function. Our preliminary data suggest that genome-wide association studies (GWAS) of diabetes and insulin-related traits are enriched for glucocorticoid genes, further confirming the overlap between these two diseases. Therefore, we hypothesize that genetic risk scores for diabetes and insulin- related traits can be used to predict glycemic response to glucocorticoids. In Specific Aim 1, we will solidify the relationship between glucocorticoid genes and diabetes by investigating how T2D genetic variation is found in glucocorticoid genes. Specifically, we will do a gene burden test on glucocorticoid related genes to evaluate if sequence variation in glucocorticoid genes differs between subjects with and without diabetes. In Specific Aim 2, we will use a biobank resource to identify subjects with and without glucocorticoid-induced hyperglycemia. We will then construct genetic risk scores (GRS) for diabetes and insulin-related phenotypes. We will determine if there is a relationship between these GRS and the development of glucocorticoid-induced hyperglycemia. We will then leverage the newfound information found in Aim 1 to create a GRS of T2D-associated glucocorticoid-related genes. We will use this novel GRS to compare subjects with and without glucocorticoid-induced hyperglycemia. Thus, we will examine both if glucocorticoid-related genes affect diabetes risk and if diabetes-related genes affect risk of glucocorticoid- induced hyperglycemia. These aims reflect a carefully planned training program directed at advancing the scientific career of the applicant. Resources at the Broad Institute and the MGH Center for Human Genetic Research and the mentorship of Jose Florez, a leading expert in the field of diabetes genetics, will allow cutting-edge genomic discovery and advanced analytical approaches to be applied to investigate the genetic variants of glucocorticoid-induced hyperglycemia.