Genetics of glucocorticoid-induced hyperglycemia

糖皮质激素引起的高血糖的遗传学

• 批准号: 9396973
• 负责人: Laura N Brenner
• 金额: $ 6.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396973
• 关键词: Adverse effects; Affect; Asthma; Autoimmune Diseases; Autoimmune Process; Beta Cell; Cell physiology; Clinical; Coma; Complication; Data; Dehydration; Development; Diabetes Mellitus; Disease; Disease Progression; Early Intervention; Early treatment; Electrolytes; Electronic Health Record; Etiology; Fellowship; Functional disorder; Genes; Genetic; Genetic Markers; Genetic Research; Genetic Risk; Genetic Variation; Genomics; Genotype; Glucagon; Glucocorticoids; Gluconeogenesis; Glucose; Glucose Transporter; Goals; Health; Heterogeneity; Hormones; Human Genetics; Hyperglycemia; Hypertension; Individual; Infection; Inflammatory; Inpatients; Institutes; Insulin; Insulin Resistance; Lead; Lipolysis; Measurement; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentorship; Methods; Molecular; Morbidity - disease rate; National Research Service Awards; Non-Insulin-Dependent Diabetes Mellitus; Outpatients; Participant; Patients; Pharmaceutical Preparations; Phenotype; Prevention; Prevention strategy; Psychotic Disorders; Research Personnel; Resources; Risk; Scientific Advances and Accomplishments; Single Nucleotide Polymorphism; Steroids; Techniques; Testing; Training; Training Programs; Variant; Weight Gain; base; biobank; career; case control; diabetes mellitus genetics; diabetes risk; exome; exome sequencing; genetic variant; genome wide association study; glucose uptake; improved; mortality; novel; response; trait; translational genetics; wound healing

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.

摘要 糖皮质激素是一种常见的药物，用于治疗无数的炎症和自身免疫性疾病。 它们的临床使用受到多种副作用的限制，最常见的是高血糖症。高血糖 已显示对疾病进展、发病率和死亡率有负面影响。大约50%的 服用糖皮质激素的患者出现高血糖，提示这种疾病的异质性。进一步 了解谁会发生高血糖症，可以预防和早期治疗， 个体 虽然糖皮质激素诱导的高血糖症的分子机制尚未完全确定， 有证据表明，这种疾病的机制反映了2型糖尿病的潜在机制 （T2D）。糖皮质激素诱导的高血糖被认为是由胰岛素抵抗增加以及 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） 的糖尿病和胰岛素相关性状中富含糖皮质激素基因，进一步证实了 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对糖皮质激素的血糖反应。 在具体目标1中，我们将通过研究糖皮质激素基因与糖尿病之间的关系， 如何在糖皮质激素基因中发现T2 D遗传变异。具体来说，我们将对以下人群进行基因负荷测试： 糖皮质激素相关基因，以评估受试者之间糖皮质激素基因的序列变异是否不同 无论是否患有糖尿病。在具体目标2中，我们将使用生物库资源来识别受试者， 没有糖皮质激素诱导的高血糖。然后，我们将构建糖尿病的遗传风险评分（GRS） 和胰岛素相关表型。我们将确定这些GRS与 糖皮质激素诱导的高血糖症的发展。然后我们将利用新发现的信息 在目的1中创建T2 D相关糖皮质激素相关基因的GRS。我们将使用这种新的GRS来 比较有和没有糖皮质激素诱导的高血糖的受试者。因此，我们将检查两者，如果 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。 这些目标反映了一个精心策划的培训计划，旨在促进科学事业的发展。 申请人。布罗德研究所和MGH人类遗传研究中心的资源以及 何塞·弗洛雷斯的指导，在糖尿病遗传学领域的领先专家，将允许尖端的基因组 发现和先进的分析方法应用于调查的遗传变异， 糖皮质激素诱导的高血糖。

项目成果

Analysis of Glucocorticoid-Related Genes Reveal CCHCR1 as a New Candidate Gene for Type 2 Diabetes.

• DOI: 10.1210/jendso/bvaa121
• 发表时间: 2020-11-01
• 期刊: Journal of the Endocrine Society
• 影响因子: 4.1
• 作者: Brenner LN;Mercader JM;Robertson CC;Cole J;Chen L;Jacobs SBR;Rich SS;Florez JC
• 通讯作者: Florez JC