Advancing Recognition and Personalized Genetic Medicine for MODY in a Multi-Ethnic US Population

项目总结/摘要 据估计，在美国，年轻人的成熟型糖尿病（MODY）约占50万例糖尿病病例。 美国的HNF 1A、HNF 4A和HNF 1B三个基因杂合突变所致MODY的遗传学诊断 GCK在临床上是可行的，允许基于遗传原因选择治疗。然而，MODY 2型糖尿病的发病率有多少？此外，种族和族裔少数群体一直受到 在MODY研究中代表性不足，导致谁可以从个性化糖尿病中受益不公平 基因医学我是芝加哥大学单基因糖尿病登记处的合作研究员。通过 在这个登记处，我跟踪了400多名因HNF 1A、HNF 4A和GCK突变而患MODY的美国个体。 利用书记官处的资源和我在吸引少数民族主体参与方面的经验， 我提出以下目标：1）前瞻性地确定少数民族受试者的MODY， 为了评估少数民族中MODY的患病率，并比较基因检测前后的血糖水平， 基因靶向糖尿病管理后的控制和糖尿病治疗满意度; 2） 比较美国少数种族和美国非少数民族之间MODY的临床特征和生物标志物， 西班牙裔白人;和3）在高临床风险的多种族美国人群中建立MODY的预测模型。 怀疑患有单基因糖尿病。我将前瞻性地识别一组患有年轻糖尿病的少数种族/族裔群体。 发病，非肥胖，非胰岛素依赖型糖尿病进行MODY基因检测。这将建立 符合MODY临床表型的种族和少数民族中MODY的患病率。MODY阳性 受试者将根据糖尿病的遗传亚型进行治疗改变， 糖化血红蛋白1和糖尿病治疗满意度评分，以评估结果和影响， 少数民族的精准医疗为了比较美国和美国之间MODY的临床特征和生物标志物， 种族/少数民族和美国非西班牙裔白人，我将使用来自单基因糖尿病的现有受试者 MODY登记研究以及目标1中前瞻性确定的受试者。我会收集更多的临床资料 数据以及血液和尿液样本，以评估高灵敏度CRP（hsCRP）的MODY生物标志物， HbA 1c、胰岛素、葡萄糖和尿C肽。这些研究将提供对潜在重要的洞察力， MODY中的种族/民族差异将影响MODY诊断的临床方法。最后，我将使用 有和无遗传定义的MODY引起的受试者的临床特征和生物标志物结果 突变，以建立一个模型，将区分个体之间的高与低的概率， MODY由于临床上可操作的形式。本申请中提出的研究将是重要的步骤 致力于解决少数民族在糖尿病精准医疗中的排斥问题，并支持美国临床医生， 准确的MODY诊断，证明基因靶向治疗和管理的临床影响 在这些重要的遗传形式的糖尿病。

Project Summary/Abstract Maturity-onset diabetes of the young (MODY) is estimated to account for ~500,000 cases of diabetes in the United States. Genetic diagnosis of MODY due to heterozygous mutations in three genes, HNF1A, HNF4A and GCK, is clinically actionable, allowing therapy selection based on the genetic cause. However, MODY is frequently misdiagnosed as type 1 or type 2 diabetes. Additionally, racial and ethnic minorities have been underrepresented in studies of MODY, resulting in inequity in who can benefit from personalized diabetes genetic medicine. I am a co-investigator of the University of Chicago Monogenic Diabetes Registry. Through this Registry, I follow over 400 US individuals with MODY due to mutations in HNF1A, HNF4A and GCK. Leveraging the resource of the Registry and my experience in engaging minority subjects to address healthcare disparities, I propose the following aims: 1) To prospective identify MODY in minority subjects in order to assess prevalence of MODY among minorities and to compare pre- and post-genetic testing glycemic control and diabetes treatment satisfaction following genetically-targeted diabetes management; 2) To compare the clinical features and biomarkers of MODY between US racial/ethnic minorities and US Non- Hispanic Whites; and 3) To build a prediction model for MODY in a multiethnic US population at high clinical suspicion for monogenic diabetes.  I will prospectively identify a cohort of racial/ethnic minorities with young- onset, non-obese, non-insulin dependent diabetes to undergo genetic testing for MODY. This will establish the prevalence of MODY among racial and ethnic minorities fitting a clinical phenotype of MODY. MODY-positive subjects will undergo treatment change based on genetic subtype of diabetes with comparison of pre- and post- HbAc1 and scores of diabetes treatment satisfaction in order to assess the outcome and impact of precision medicine in minorities. In order to compare clinical features and biomarkers of MODY between US racial/ethnic minorities and US Non-Hispanic Whites, I will use existing subjects from the Monogenic Diabetes Registry with MODY as well as those subjects prospectively identified in aim 1. I will collect additional clinical data and blood and urine samples in order to assess MODY biomarkers of high sensitivity CRP (hsCRP), HbA1c, insulin and glucose and urine c-peptide. These studies will provide insight into potentially important racial/ethnic differences in MODY that will impact clinical approaches to MODY diagnosis. Finally, I will use clinical features and biomarker results from subjects with and without genetically defined MODY-causing mutations in order to build a model that will discriminate between individuals with high versus low probability of MODY due to clinically-actionable forms. The studies proposed in this application will be important steps towards addressing exclusion of minorities in diabetes precision medicine and supporting US clinicians in accurate MODY diagnosis, demonstrating the clinical impact of genetically targeted therapy and management in these important genetic forms of diabetes.