Polygenic Hyperlipidemias and Coronary Artery Disease Risk
Polygenic Hyperlipidemias and Coronary Artery Disease Risk
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DOI：
10.1161/circgen.119.002725
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发表时间：
2020-04-01
影响因子：
7.4
通讯作者：
Ripatti, Samuli
中科院分区：
文献类型：
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作者：
Ripatti, Pietari;Ramo, Joel T.;Ripatti, Samuli
背景：高脂血症是冠状动脉疾病（CAD）的高度遗传性危险因素。虽然单基因家族性高胆固醇血症与严重增加的 CAD 风险相关，但目前尚不清楚大量 LDL（低密度脂蛋白）胆固醇 (LDL-C) 或甘油三酯 (TG) 增加的变异体在多大程度上与 CAD 风险增加相关。 方法：我们针对 LDL-C 和 TG 分别推导了大约 6M 种多基因风险评分 (PRS)，权重来自英国生物银行大约 324K 样本的全基因组关联研究。我们评估了多基因高胆固醇血症和高甘油三酯血症对国家 FINRISK 研究 (FINRISK) 队列中 27 039 名个体的血脂水平以及 FinnGen 项目 (FinnGen) 中 135 638 名个体（13 753 CAD 病例）的 CAD 风险的影响。 结果：在 FINRISK 中，中位 LDL-C 为 3.39（95% CI， 3.38-3.40) mmol/L，LDL-C PRS 分布的最低和最高 5% 之间的范围为 2.87 (95% CI, 2.82-2.94) 至 3.78 (95% CI, 3.71-3.83) mmol/L。 TG PRS 的中位 TG 为 1.19 (95% CI, 1.18-1.20) mmol/L，范围为 0.97 (95% CI, 0.94-1.00) 至 1.55 (95% CI, 1.48-1.61) mmol/L。在 FinnGen 中，将最高 5% 的 PRS 与最低 95% 进行比较，LDL-C PRS 的 CAD 比值比为 1.36（95% CI，1.24-1.49），TG PRS 的 CAD 比值比为 1.31（95% CI，1.19-1.43）。 These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS).Conclusions:The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS。与 CAD 的 PRS 相比，脂质 PRS 指出已知且可直接修改的风险因素，为临床转化提供额外指导。
Background:Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk.Methods:We derived polygenic risk scores (PRSs) with approximate to 6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with approximate to 324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen).Results:In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS).Conclusions:The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.