Abstract Body: Background
Stroke patients are at risk for secondary vascular events, but risk factor control is often insufficient. Vascular risk factors like hypertension, diabetes, and hyperlipidemia are highly heritable, and persons with higher polygenic predisposition are less likely to achieve risk factor control. The combined impact of these polygenic effects on clinical management of stroke patients is unknown.
Hypothesis
We hypothesize that the combined polygenic effect of the most important vascular risk factors leads to higher rates of treatment failure and secondary vascular events in stroke survivors.
Methods
In our genetic association study in stroke patients (ischemic or hemorrhagic) from the UK Biobank, we created polygenic risk scores (PRS) for systolic blood pressure, diabetes, and LDL from genome-wide association summary statistics. We added them to a metaPRS for overall genetic risk for all three risk factors, categorized into low, intermediate, and high risk (<20, 20-80, >80^th percentiles). Outcomes at baseline were uncontrolled (at least one of: systolic blood pressure >140mmHg, HbA1c >7.0%, or LDL >100mg/dl) and resistant risk factors (uncontrolled despite treatment). Longitudinal outcomes were recurrent stroke, myocardial infarction, and all-cause death, from via EHR follow-up. We performed logistic regression adjusted to age, sex, and genetic principal components to assess the relationship between the metaPRS and outcomes.
Results
In 6,290 stroke patients (mean age 61, female sex 42%), high polygenic risk was associated with 37% increase in uncontrolled (OR 1.37, 95% CI 1.16-1.63, p-trend <0.001) and a 2-fold increase in resistant risk factors (OR 2.09, 95% CI 1.77-2.48, p-trend <0.001). Poor risk factor control translated into clinical outcomes: high polygenic risk was associated with a 20% increase of recurrent stroke (OR 1.21, 95% CI 0.99-1.48, p-trend 0.05), 58% increase of myocardial infarction (OR 1.58,95% CI 1.13-2.23, p-trend 0.02), 31% increase of death (OR 1.31,95% CI 1.07-1.60, p-trend 0.02), and 35% higher composite risk of any events (OR 1.35, 95% CI 1.14-1.60, p-trend <0.001, see Table).
Conclusion
In our study, aggregate polygenic risk for three main vascular risk factors correlates with poor risk factor control and treatment resistance in stroke patients, but also with recurrent stroke, myocardial infarction, and death. Further research should evaluate the benefit of tailored therapies for stroke survivors with adverse genomic profiles.