Background:Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable; however, current risk stratification tools (CHA₂DS₂-VASc) do not include family history or genetic risk. We hypothesized that we could improve ischemic stroke prediction in patients with AF by incorporating polygenic risk scores (PRS).Methods:Using data from the largest available genome-wide association study in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank, both independently and integrated with clinical risk factors. The integrated PRS and clinical risk factors risk tool had the greatest predictive ability.Results:Compared with the currently recommended risk tool (CHA₂DS₂-VASc), the integrated tool significantly improved Net Reclassification Index (2.3% [95% CI, 1.3%–3.0%]) and fit (χ²P=0.002). Using this improved tool, >115 000 people with AF would have improved risk classification in the United States. Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (hazard ratio, 1.13 per 1 SD [95% CI, 1.06–1.23]). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson correlation coefficient, −0.018).Conclusions:In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors; however, the prediction of stroke remains challenging.

中文翻译：

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结合临床和多基因风险可改善心房颤动患者的中风预测

背景：心房颤动（AF）与缺血性卒中风险增加五倍相关。这种风险的一部分是可遗传的；然而，目前的风险分层工具（CHA ₂ DS ₂-VASc) 不包括家族史或遗传风险。我们假设我们可以通过整合多基因风险评分 (PRS) 来改善 AF 患者的缺血性卒中预测。方法：使用来自欧洲最大的可用全基因组关联研究的数据，我们结合了超过 50 万个基因变异来构建 PRS预测 AF 患者的缺血性卒中。我们在来自 UK Biobank 的独立数据中对这一 PRS 进行了外部验证，这些数据独立并与临床风险因素相结合。综合 PRS 和临床风险因素风险工具具有最大的预测能力。 结果：与目前推荐的风险工具（CHA ₂ DS ₂-VASc)，集成工具显着提高了净重分类指数 (2.3% [95% CI, 1.3%–3.0%]) 和拟合 (χ ² P =0.002)。使用这种改进的工具，美国超过 115 000 名 AF 患者的风险分类将得到改善。独立地，PRS 是前瞻性 AF 患者缺血性卒中的重要预测因子（风险比，1.13/1 SD [95% CI，1.06-1.23]）。最后，多基因风险评分与临床风险因素不相关（Pearson 相关系数，-0.018）。结论：在 AF 患者中，PRS 与缺血性卒中风险之间似乎存在显着关联。结合 PRS 和临床危险因素发现了最大的预测能力；然而，中风的预测仍然具有挑战性。