增强型多基因风险评分与生活方式对心血管疾病、糖尿病和血脂水平的交互作用。
Interactions Between Enhanced Polygenic Risk Scores and Lifestyle for Cardiovascular Disease, Diabetes, and Lipid Levels.
机构信息
Program of Computational Biology and Bioinformatics (Y.Y., H.Z.), Yale University.
Department of Statistics and Data Science (X.C., J.H.), Yale University.
出版信息
Circ Genom Precis Med. 2021 Feb;14(1):e003128. doi: 10.1161/CIRCGEN.120.003128. Epub 2021 Jan 12.
BACKGROUND
Both lifestyle and genetic factors confer risk for cardiovascular diseases, type 2 diabetes, and dyslipidemia. However, the interactions between these 2 groups of risk factors were not comprehensively understood due to previous poor estimation of genetic risk. Here we set out to develop enhanced polygenic risk scores (PRS) and systematically investigate multiplicative and additive interactions between PRS and lifestyle for coronary artery disease, atrial fibrillation, type 2 diabetes, total cholesterol, triglyceride, and LDL-cholesterol.
METHODS
Our study included 276 096 unrelated White British participants from the UK Biobank. We investigated several PRS methods (P+T, LDpred, PRS continuous shrinkage, and AnnoPred) and showed that AnnoPred achieved consistently improved prediction accuracy for all 6 diseases/traits. With enhanced PRS and combined lifestyle status categorized by smoking, body mass index, physical activity, and diet, we investigated both multiplicative and additive interactions between PRS and lifestyle using regression models.
RESULTS
We observed that healthy lifestyle reduced disease incidence by similar multiplicative magnitude across different PRS groups. The absolute risk reduction from lifestyle adherence was, however, significantly greater in individuals with higher PRS. Specifically, for type 2 diabetes, the absolute risk reduction from lifestyle adherence was 12.4% (95% CI, 10.0%-14.9%) in the top 1% PRS versus 2.8% (95% CI, 2.3%-3.3%) in the bottom PRS decile, leading to a ratio of >4.4. We also observed a significant interaction effect between PRS and lifestyle on triglyceride level.
CONCLUSIONS
By leveraging functional annotations, AnnoPred outperforms state-of-the-art methods on quantifying genetic risk through PRS. Our analyses based on enhanced PRS suggest that individuals with high genetic risk may derive similar relative but greater absolute benefit from lifestyle adherence.
背景
生活方式和遗传因素都会增加心血管疾病、2 型糖尿病和血脂异常的风险。然而，由于之前遗传风险估计不佳，这两组风险因素之间的相互作用尚未得到全面了解。在这里，我们着手开发增强型多基因风险评分（PRS），并系统地研究 PRS 与生活方式对冠心病、心房颤动、2 型糖尿病、总胆固醇、甘油三酯和 LDL 胆固醇的乘法和加法相互作用。
方法
我们的研究包括来自英国生物库的 276096 名无血缘关系的白种英国人。我们研究了几种 PRS 方法（P+T、LDpred、PRS 连续收缩和 AnnoPred），并表明 AnnoPred 始终能提高所有 6 种疾病/特征的预测准确性。利用增强型 PRS 以及根据吸烟、体重指数、身体活动和饮食分类的综合生活方式状况，我们使用回归模型研究了 PRS 和生活方式之间的乘法和加法相互作用。
结果
我们发现，健康的生活方式降低了不同 PRS 组的疾病发病率，其乘法效应相似。然而，在 PRS 较高的个体中，生活方式的坚持带来的绝对风险降低更为显著。具体来说，对于 2 型糖尿病，在 PRS 最高的 1%中，生活方式的坚持可降低 12.4%（95%置信区间，10.0%-14.9%）的绝对风险，而在 PRS 最低的十分位数中，仅降低 2.8%（95%置信区间，2.3%-3.3%），这导致比值大于 4.4。我们还观察到 PRS 与生活方式对甘油三酯水平的交互作用具有显著影响。
结论
通过利用功能注释，AnnoPred 在通过 PRS 量化遗传风险方面优于最先进的方法。我们基于增强型 PRS 的分析表明，遗传风险较高的个体可能会从生活方式的坚持中获得相似的相对但更大的绝对益处。
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