Abstract DP264: Genetic Predisposition to Type 2 Diabetes Increases Stroke Risk Across Diverse Populations

Introduction: Type 2 diabetes (T2D) is a risk factor for stroke, with large-scale studies suggesting shared genetic susceptibility. A higher T2D polygenic risk score (PRS) has been linked to higher stroke risk, but this relationship has not been comprehensively evaluated in diverse populations. We investigated whether genetic predisposition to T2D is associated with incident stroke in the Multiethnic Cohort Study (MEC) and explored potential effect modification by race/ethnicity, known T2D, smoking status, and diet quality. Methods: We performed a nested cohort study of MEC participants recruited from Hawaii and Los Angeles identifying as Native Hawaiian, Japanese, Hispanic/Latino, Black, and White. Eligible participants were Medicare beneficiaries with hospital discharge data, no baseline history of stroke, and available genotyping data. Genetic predisposition to T2D was quantified using a validated multiethnic T2D PRS, analyzed both continuously and by quartiles. Associations between T2D PRS and incident stroke were assessed using Cox proportional hazards models, adjusting for age, sex, race/ethnicity, BMI, and the first genetic principal components to account for population stratification. Effect modification was evaluated via product terms. Results: Among 33,385 participants (mean age of 67.7±4.4 years; 52.6% female; 7.3% Native Hawaiian, 43.2% Japanese, 16.8% Hispanic/Latino, 10.7% Black, and 22.0% White), 8,502 incident strokes occurred during follow-up (25.5%; mean age of 78.6±7.2 years). Higher T2D PRS was associated with higher risk of ischemic stroke, both continuously (HR 1.04, 95% CI 1.02—1.07, p=0.001) and by quartiles (Q3 HR 1.12, 95% CI 1.05—1.20, p<0.001; Q4 HR 1.13, 95% CI 1.06—1.21, p<0.001; referent category: Q1). Race/ethnicity, smoking status, and diagnosed T2D did not significantly modify this association. Diet quality, measured by the Healthy Eating Index, appeared to attenuate stroke risk among those in intermediate PRS categories (product term p-value=0.02). Conclusions: In a large multiethnic cohort, genetic predisposition to T2D was associated with higher incident stroke risk, regardless of race/ethnicity or clinical diabetes status. Diet quality may mitigate this risk among individuals with intermediate genetic susceptibility. These findings suggest that integrating genetic risk assessment with lifestyle interventions may enhance stroke prevention strategies in diverse populations.