Recurrent Stroke Prediction by Applying a Stroke Polygenic Risk Score in the Japanese Population

Recently, various polygenic risk score (PRS)-based methods were developed to improve stroke prediction. However, current PRSs (including cross-ancestry PRS) poorly predict recurrent stroke. Here, we aimed to determine whether the best PRS for Japanese individuals can also predict stroke recurrence in this population by extensively comparing the methods and maximizing the predictive performance for stroke onset.

We used data from the disease-oriented BBJ1 (BioBank Japan first cohort; recruited between 2003 and 2007, n=179 938) to derive and optimize the PRSs using a 10-fold cross-validation. We integrated the optimized PRSs for multiple traits, such as vascular risk factors and stroke subtypes to generate a single PRS using the meta-scoring approach (metaGRS). We used an independent BBJ2 (BBJ second cohort; recruited between 2012 and 2017, n=41 929) as a test sample to evaluate the association of the metaGRS with stroke and recurrent stroke. In addition, we analyzed its association stratified by risk factors. We administered 3 distinct tests to consider the potential index event bias.

We analyzed recurrent stroke cases (n=174) and nonrecurrent stroke controls (n=1153) among subjects within the BBJ2. After adjusting for known risk factors, metaGRS was associated with stroke recurrence (adjusted odds ratio per SD, 1.18 [95% CI, 1.00-1.39]; P=0.044), although no significant correlation was observed with the published PRSs. The outcomes derived from these examinations did not provide any significant indication of the influence of index event bias. The high metaGRS group without a history of hypertension had a higher risk of stroke recurrence than that of the low metaGRS group (adjusted odds ratio, 2.24 [95% CI, 1.07-4.66]; P=0.032). There was no association at all in the hypertension group (adjusted odds ratio, 1.21 [95% CI, 0.69-2.13]; P=0.50).

The metaGRS developed in a Japanese cohort predicted stroke recurrence in an independent cohort of patients. In particular, it predicted an increased risk of recurrence among stroke patients without hypertension. These findings provide clues for additional genetic risk stratification and help in developing personalized strategies for stroke recurrence prevention.