Background:The clinical implications of a polygenic risk score (PRS) for LDL-C (low-density lipoprotein cholesterol) are not well understood, both within the general population and individuals with familial hypercholesterolemia (FH).Methods:We developed the LDL-C PRS using Least Absolute Shrinkage and Selection Operator regression in 377 286 White British participants from UK Biobank and tested its association with LDL-C according to FH variant carrier status in another 41 748 whole-exome sequenced individuals. Next, we tested for an enrichment of FH variant carriers among individuals with severe hypercholesterolemia and low LDL-C PRS. Last, we contrasted the effect of the LDL-C PRS, measured LDL-C and FH variant carrier status on risk of ischemic heart disease among 3010 cases and 38 738 controls.Results:Among the 41 748 whole-exome sequenced White British individuals, 1-SD increase in the LDL-C PRS was associated with elevated LDL-C among both FH variant carriers (0.34 [95% CI, 0.22–0.47] mmol/L) and noncarriers (0.42 [95% CI, 0.42–0.43] mmol/L). Among individuals with severe hypercholesterolemia, FH variant carriers were enriched in those with a low LDL-C PRS (odds ratio, 2.20 [95% CI, 1.66–2.71] per SD). Each SD increase in the LDL-C PRS was associated with risk of ischemic heart disease to the comparable magnitude as measured LDL-C (odds ratio, 1.24 [95% CI, 1.20–1.29] and odds ratio, 1.15 [95% CI, 1.09–1.23], respectively). The LDL-C PRS was not strongly associated with other traditional ischemic heart disease risk factors.Conclusions:An LDL-C PRS could be used to identify individuals with a higher probability of harboring FH variants. The association between ischemic heart disease and the LDL-C PRS was comparable to measured LDL-C, likely because the PRS reflects lifetime exposure to LDL-C levels.

中文翻译：

---

低密度脂蛋白胆固醇的多基因风险评分与缺血性心脏病的风险相关，并富含家族性高胆固醇血症的个体

背景：对于 LDL-C（低密度脂蛋白胆固醇）的多基因风险评分 (PRS) 的临床意义尚不清楚，无论是在普通人群还是家族性高胆固醇血症 (FH) 患者中。方法：我们开发了 LDL- C PRS 在来自 UK Biobank 的 377 286 名英国白人参与者中使用最小绝对收缩和选择算子回归，并在另外 41 748 名全外显子组测序个体中根据 FH 变异携带者状态测试了其与 LD​​L-C 的关联。接下来，我们测试了在患有严重高胆固醇血症和低 LDL-C PRS 的个体中 FH 变异携带者的富集。最后，我们比较了 LDL-C PRS、测量的 LDL-C 和 FH 变异携带者状态对 3010 例病例和 38738 例对照者缺血性心脏病风险的影响。结果：在 41 748 名全外显子组测序的英国白人个体中，LDL-C PRS 增加 1-SD 与 FH 变异携带者的 LDL-C 升高相关（0.34 [95% CI，0.22–0.47] mmol/L）和非携带者（0.42 [95% CI，0.42–0.43] mmol/L）。在患有严重高胆固醇血症的个体中，FH 变异携带者在低 LDL-C PRS 的人群中富集（比值比，2.20 [95% CI，1.66-2.71] per SD）。LDL-C PRS 的每个 SD 增加与缺血性心脏病的风险相关，与测量的 LDL-C 相当（优势比，1.24 [95% CI，1.20-1.29] 和优势比，1.15 [95% CI， 1.09–1.23]，分别）。LDL-C PRS 与其他传统的缺血性心脏病风险因素没有很强的相关性。结论：LDL-C PRS 可用于识别具有较高概率携带 FH 变异的个体。