Diabetes (DM) complications are the major cause of its morbidity, mortality, and costs. MVP009 has advanced understanding of the underlying genetics. Since DM care does not take advantage of progress in genetics, we propose to use genetics to support both clinical translation and mechanistic discovery. In MVP009, we utilized highly specific phenotypes in genome-wide association studies (GWAS) of (i) heart failure (HF) with preserved vs. reduced ejection fraction; (ii) hypoglycemia – severe (emergency visits) and incidental (outpatient visits); (iii) kidney disease; and (iv) eye disease. We also found that although typical, “juvenile-onset type 1 diabetes (T1D)” excludes military service, at least 10% of Veterans with presumed T2D in MVP may have “adult onset T1D” – largely unrecognized. We now propose to extend these findings. Consistent with the Precision Medicine in Diabetes Consensus Report, our Aims target precision in (i) diagnosis (genetic T1D vs. T2D), (ii) treatment [combining genetic with traditional risk factors (RF)], and (iii) prognosis (epigenomic contributions to complications) – to incorporate genetics so that care can be more accurate and individualized, and identify mechanisms that can lead to discovery of new treatments. Aim 1: Assess the contributions of T1D and T2D genetic loads to the clinical characteristics and disease trajectories of people presumed to have T2D. We will model multiethnic genetic risk with T1D and T2D polygenic risk scores (PRS, with multiethnic data from large recent studies); each MVP Veteran will have both a T1D and a T2D PRS. Outcomes will include incident DM, and the disease trajectory: age and BMI at onset, time to insulin Rx, and ketoacidosis and hypoglycemia. We will evaluate the utility of the PRS to identify Veterans with DM who would benefit from definitive T1D testing and/or early use of insulin. Aim 2: Assess the combined contributions of genetic/nongenetic RF to development of complications. (SubAim a) Identify effect modifications between RF and complications. Genetic interaction analyses will include lifestyle, demographics, and comorbidities (e.g., blood pressure, HbA1c), as modifiers of the risk of complications conferred by disease loci and PRS. We will use both hypothesis-testing approaches for known loci and PRS, and hypothesis-generating approaches (using genome-wide G×E modeling) to examine interactions associated with diabetic eye disease (DED), kidney disease (DKD), HF, and hypoglycemia, and causal associations using state-of-the-art Mendelian Randomization (MR), including multivariable and mediation MR. (SubAim b) Develop and test predictive models. We will use summary statistics from the MVP GWAS and the literature, to develop separate PRS using the “best practice” recent method, for DED, DKD, HF, and hypoglycemia, and PheWAS with the PRSs to elucidate previously unknown RFs. Utilizing the PRS, PheWAS, information from SubAim (a), clinical RF, and treatments, we will develop genome-informed predictive models that will be evaluated in eMERGE and more recent MVP participants. Aim 3: Identify epigenomic markers and molecular systems underlying DM complications. Epigenomic changes regulate gene expression, can mediate environmental and physiologic effects, and have been associated with T2D and related glycemic traits. We hypothesize that differential methylation will also be associated with DM complications. Methylation information using the EPIC chip (>850,000 sites) will be available on >30,000 Veterans, and can be imputed in other Veterans, allowing epigenomic and multi-omic methods such as aggregation analysis and epigenome-wide association studies to (i) identify associations with the complications of DM as well as hypoglycemia, and (ii) identify the genes and pathways involved. Impact: The genetics of diagnosis, G×E, epigenomics, and predictive models should both aid translation – to identify risk in individuals, and help personalize treatment to reduce DM complications and hypoglycemia – and support discovery of new therapies to mitigate the underlying processes.

Diabetes (DM) complications are the major cause of DM morbidity, mortality, and costs. As current care does not take advantage of progress in genetics, we will incorporate genetics. Since Veterans thought to have type 2 DM may also have genes for type 1 DM, we will assess the contributions of these genetic loads to the patterns of disease. To account for a wide range of risk, we will assess the combined contributions of genetic and nongenetic risk factors to the DM complications of eye and kidney disease, hypoglycemia, and heart failure, including development and testing of predictive models. Since changes to our DNA can alter what our genes do, we will identify “epigenomic” markers and molecular systems underlying DM complications. Our study of the genetics of diagnosis, gene-environment interactions, epigenomics, and predictive models should both aid translation – to identify risk in individuals, and help personalize treatment to reduce DM complications and hypoglycemia – and support discovery of new therapies to mitigate the underlying processes.