GENETIC AND EPIGENETIC ARCHITECTURE OF TYPE 2 DIABETES SUBTYPES IN THE MIDDLE EASTERN QATARI POPULATION

Abstract

Type 2 diabetes (T2D) can be classified into SIDD, SIRD, MOD, and MARD. This classification can help in predicting disease complications and determining the best treatment for individuals. However, the applicability of this classification to non-European populations and sensitivity to confounding factors remain unclear. The k-means clustering was applied to a large Middle Eastern Qatar biobank cohort. The four T2D subtypes were identified within a large Arab cohort. Data-derived centers outperformed European coordinates in classifying T2D. The use of actual age, as opposed to age of diagnosis, impacted mostly MOD and MARD classification. Obesity prevalence was significantly higher in females. However, that did not translate to worse disease severity, as indicated by comparable levels of HbA1C and HOMA2-IR. Interestingly, most MODY individuals were clustered within MARD, further highlighting the need for precise classification and tailored interventions. Individuals who are at a higher risk of CKD and MASLD may require closer monitoring and physician oversight. The PRS and GWAS analysis replication of T2D risk across subtypes and T2D-associated variants in each subtype was evaluated. The findings highlight the genetic contribution to different T2D subtypes and present potential pathways affected in each subtype. The methylation analysis of T2D subtypes in the QBB cohort has shown differences in the methylation among T2D subtypes, in which only T2D SIDD has shown a significant hypomethylation in TXNIP gene. The T2D subtypes MOD and MARD showed a lower dysregulation of methylation compared to SIDD and SIRD. This study has combined the knowledge of T2D subclassifications with their genetic and epigenetic profiles to provide a roadmap for more personalized characterization of T2D individuals, facilitating the advancement of precision medicine approaches.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences