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

项目摘要/摘要 据估计，青年成熟期起病糖尿病(MODY)占全球约500,000例糖尿病患者 美国。HNF1a、HNF4a和HNF4a基因杂合性突变所致MODY的基因诊断 GCK在临床上是可操作的，允许根据遗传原因选择治疗方法。然而，MODY是 经常被误诊为1型或2型糖尿病。此外，种族和少数民族一直是 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的不公平 基因医学。我是芝加哥大学单基因糖尿病登记处的共同研究员。穿过 在这个注册中心，我跟踪了400多名因HNF1a、HNF4a和GCK突变而患有MODY的美国人。 利用书记官处的资源和我在吸纳少数群体主题方面的经验 医疗保健差异，我提出以下目标：1)前瞻性地识别少数民族人群中的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 基因靶向糖尿病治疗后的控制和糖尿病治疗满意度；2) 美国少数民族和非少数民族MODY的临床特征和生物标志物的比较 西班牙裔白人；以及3)在临床高度的美国多民族人群中建立MODY的预测模型 怀疑为单基因糖尿病。 I将前瞻性地确定一组年轻的种族/少数民族- 起病、非肥胖、非胰岛素依赖型糖尿病患者需接受MODY基因检测。这将确立 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基因亚型进行治疗变化，比较治疗前和治疗前 治疗后HbAc1和糖尿病治疗满意度评分，以评估治疗结果和影响 少数民族的精准医疗。为比较美、美两国MODY的临床特点和生物标志物 种族/少数民族和美国非西班牙裔白人，我将使用单基因糖尿病的现有受试者 在MODY注册以及在AIM 1中预期确定的受试者。我将收集更多的临床数据 数据以及血液和尿样，以评估高敏C反应蛋白(HsCRP)的MODY生物标记物， 糖化血红蛋白、胰岛素、血糖、尿C-肽。这些研究将提供对潜在重要的 MODY的种族/民族差异将影响MODY的临床诊断方法。最后，我将使用 遗传性和非遗传性MODY患者的临床特征和生物标记物结果 突变，以建立一个模型，区分高概率和低概率的个体 由于临床上可操作的形式而导致的MODY。在这项申请中提出的研究将是重要的步骤 朝着解决糖尿病精准医学中少数族裔被排斥的问题并支持美国临床医生 准确的MODY诊断，展示了基因靶向治疗和管理的临床影响 在这些重要的糖尿病基因形式中。

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.