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

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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.