Pathway‐Specific Polygenic Risk Score and Risk of Hyperglycaemic Progression in Patients With Type 2 Diabetes

Aim Pathway‐specific polygenic risk scores (psPRS) provide insights into the heterogeneity of type 2 diabetes. We aim to study whether psPRS for beta cell dysfunction, obesity and metabolic syndrome associate with risk of hyperglycaemic progression in Southeast Asian patients with type 2 diabetes. Participants and Methods One thousand and fifty‐nine insulin‐naïve outpatients with type 2 diabetes were enrolled from a secondary hospital and a primary care facility. The psPRS were constructed as a weighted sum of risk alleles associated with specific metabolic pathways. Hyperglycaemic progression was defined as sustained insulin therapy lasting longer than 6 months. Results During a median of 11.2 (8.9–11.8) years of follow‐up, 188 participants initiated sustained insulin therapy. One SD increment in psPRS for metabolic syndrome was associated with a 17% increased risk for hyperglycaemic progression after adjustment for clinical risk factors (adjusted HR 1.17 [1.02–1.36]). Consistent results were obtained when hyperglycaemic progression was defined as a composite of sustained insulin therapy and requirement for insulin treatments (HbA1c > 8.5% with two or more non‐insulin medications). Adding metabolic syndrome psPRS onto clinical risk predictors (diabetes onset age, HbA1c, HDL cholesterol, eGFR, urinary albumin‐to‐creatinine ratio) did not improve risk discrimination (delta AUC −0.01 [95% CI −0.02 to 0.01], p = 0.50). Neither psPRS for beta cell dysfunction nor obesity was associated with the risk of hyperglycaemic progression. Conclusion psPRS for metabolic syndrome is nominally associated with risk of hyperglycaemic progression in multi‐ancestry Southeast Asian people with type 2 diabetes. The psPRS does not provide incremental value for prediction of hyperglycaemic progression beyond clinical risk predictors.