Polygenic Susceptibility to Diabetes and Poor Glycemic Control in Stroke Survivors

Abstract

Background and objectives: Type 2 diabetes mellitus (T2DM) is highly genetically determined, and polygenic susceptibility to T2DM (PSD) increases the risk of worse glycemic control and adverse vascular outcomes. Its role in stroke patients remains unknown. We aim to determine whether higher PSD is associated with worse glycemic control in stroke survivors.

Methods: We conducted a 2-stage genetic association study. In a cross-sectional design, we selected stroke survivors from the UK Biobank (enrollment between 2006 and 2010) to evaluate the relationship between PSD and glycemic control. Second, we replicated the results using data from All of Us (enrollment between 2018 and 2022). Exposures were low, intermediate, and high PSD, modeled through percentiles (<20, 20-80, >80) of a polygenic risk score of 2,522 independent risk variants associated with T2DM at genome-wide levels (p < 5 × 10^-8). Outcomes were hemoglobin A1c (HbA1c) levels, uncontrolled diabetes (HbA1c ≥7.0%), and resistant diabetes (uncontrolled despite antidiabetic treatment).

Results: Stage 1 included 6,908 stroke survivors (mean age 61 years, 42% female), including 977 (14%) with diabetes. Compared with low PSD, participants with high PSD had an increase of 0.49 in HbA1c (β = 0.49, standard error 0.03, p-trend <0.001), 6.9 times the odds of uncontrolled diabetes (odds ratio [OR] 6.92, 95% CI 4.71-10.52), and 7.8 times the odds of resistant diabetes (OR 7.76, 95% CI 4.92-12.89). Stage 2 (replication) confirmed the association with HbA1c in 4,451 stroke survivors, including 2,163 (49%) with diabetes (mean age 64 years, 53% female, p-trend <0.05 for all tests).

Discussion: Among stroke survivors, a higher PSD was associated with poorer glycemic control. Further research should determine precision medicine strategies using PSD to improve clinical management of stroke patients.