Hyperglycemia in Turner syndrome: Mechanisms and X chromosome contributions - PROJECT SUMMARY/ABSTRACT Turner syndrome (TS) is a common genetic disorder caused by X chromosome (Xchr) abnormalities. Women with TS have a four-fold higher risk of developing diabetes mellitus (DM) than the general population, and DM contributes significantly to mortality. Despite the prevalence of DM in TS, the underlying mechanism(s) and specific Xchr contributions driving diabetes risk remain elusive. As such, there are no specific preventative strategies or treatments for DM in TS. The objective of the proposed project is to unravel the genetic and physiologic mechanism(s) that lead to hyperglycemia in TS, using glycemic phenotyping in the context of Xchr gene dosage, Xchr parent-of-origin, and genomic and epigenetic techniques. My central hypotheses are that TS-associated hyperglycemia is a consequence of altered Xchr gene dosage (e.g., by Xchr imprinting and/or structural Xchr variation) and that this contributes to a TS-specific phenotype of progressive beta cell functional impairments first detectable only in response to oral glucose but not mixed macronutrients. To test these hypotheses, we propose the following aims: (1) Identify Xchr contributions to the TS hyperglycemia phenotype and (2) Determine if beta cell function is impaired in response to mixed macronutrients in TS. We will perform multivariable analysis of data from National Institute of Child Health and Human Development’s Data and Specimen Hub, which includes frequently sampled oral glucose tolerance tests (fsOGTT) and Xchr parent-of- origin for 84 individuals with TS to determine if an Xchr parent-of-origin effect exists with respect to categorical glycemia. Additionally, we will enroll 30 individuals with TS to undergo long-read Xchr sequencing in conjunction with RNA sequencing. This will allow identification of candidate imprinted Xchr genes. This project also includes paired fsOGTT and mixed meal tolerance tests (MMTT) for 20 individuals with TS and 10 age-, sex-, and BMI- matched controls to further elucidate TS-specific impairments in beta cell function. Completion of the proposed project will add to understanding of Xchr contributions to the TS hyperglycemia phenotype and contribute toward identification of drug targets and/or new disease managements strategies. The project is also a vehicle for me to achieve my career goals and objectives by providing me with expertise in glycemic phenotyping, genomic and epigenetic techniques, multivariable statistics, and multisite study design and execution. The proposed integrated research, mentorship, and didactic training program combined with the collaborative research environment at the University of Iowa and off-site collaboration with faculty at the University of Minnesota and Indiana University will foster my long-term career goal of becoming an independent investigator leading a translational research program focused on isolating genomic and epigenetic contributions to diabetes risk.
