Molecular Prediction, Disease Progression, and Type 2 Diabetes (T2D) Phenotypes in South Asians

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY Type 2 Diabetes (T2D) and prediabetes are characterized by substantial heterogeneity. Evidence indicates that T2D is comprised of several phenotypic subgroups with diverse clinical characteristics, disease progression, treatment responses, and risks of complications. Nevertheless, significant gaps persist in our understanding of the biological underpinnings, molecular mechanisms, and translational implications of T2D phenotypes, particularly in non-European populations like South Asians. This population is at high risk for both T2D and prediabetes and exhibits unique phenotypic manifestations. In our preliminary investigations, we demonstrated that, unlike Europeans, where insulin resistance primarily drives the pathophysiology, South Asians present a notably higher prevalence of mild and severe insulin deficient T2D phenotypes (79%). Most significantly, these phenotypes were found to be responsible for ~ 82% of diabetes-related mortality cases. Additionally, among participants with prediabetes, 64% showed the attributes of an insulin deficiency phenotype, contributing to ~74% of incident diabetes cases. Currently, uncertainties remain regarding genetic patterns distinguishing prediabetes and T2D phenotypes and the predictive potential of genetic or metabolomic factors in the progression to T2D. To address these gaps, we propose leveraging the NHLBI-funded PPG, the Precision- CARRS cohort (P01HL154996), consisting of ~20,000 individuals with over 13 years of follow-up and banked biospecimens, including 6,237 T2D and 8,381 prediabetes cases. Our aims are to: (Aim-1) Investigate genetic associations with T2D and prediabetes phenotypes, develop polygenic risk scores, and explore the associations between genetic factors and glycemic trajectories; (Aim-2) Assess associations of metabolomic markers and develop metabolite scores using a high-resolution untargeted approach and examine their relationship with glycemic trajectories; (Aim-3) Evaluate the predictive utility of genetic variants and plasma metabolites, in conjunction with traditional diabetes risk factors, for distinguishing incident T2D cases. We will also assess the predictive utility of the identified genetic and metabolomic markers with the incident cardiovascular outcomes. This project will facilitate significant progress in translational precision medicine and public health, deepening our understanding of the intrinsic genomic and phenotypic heterogeneity that underlies novel T2D and prediabetes phenotypes in this under-represented high-risk population. Through these efforts, we will advance the prevention and management of prediabetes and T2D, leading to personalized and precise disease prediction and early-stage detection.