Subtyping Severe Hypercholesterolemia by Genetic Determinant to Stratify Risk of Coronary Artery Disease.
Subtyping Severe Hypercholesterolemia by Genetic Determinant to Stratify Risk of Coronary Artery Disease.
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通过遗传决定因素对严重高胆固醇血症进行亚型分类，以分层冠状动脉疾病的风险。
DOI：
10.1161/atvbaha.123.319341
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Oetjens,MatthewT
中科院分区：
文献类型：
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作者：
Berry,AlexanderSF;Jones,LaneyK;Sijbrands,EricJ;Gidding,SamuelS;Oetjens,MatthewT
背景严重高胆固醇血症，定义为 LDL（低密度脂蛋白）胆固醇 (LDL-C) 测量值≥190 mg/dL，与冠状动脉疾病 (CAD) 风险增加相关。严重高胆固醇血症的原因包括单基因家族性高胆固醇血症、多基因高胆固醇血症、脂蛋白(a) [Lp(a)]升高高胆固醇血症、多基因高胆固醇血症伴Lp(a)升高（二次）或非遗传性高胆固醇血症。使用遗传学方法对严重高胆固醇血症患者的 CAD 事件风险进行分层与单独使用 LDL-C 水平进行风险分层相比，其附加值尚不清楚。 方法 为了确定按遗传原因进行风险分层是否比 LDL-C 水平提供更好的 10 年 CAD 事件风险分层，我们进行了一项回顾性队列研究，比较了严重高胆固醇血症亚型（遗传性和非遗传性原因）之间的 CAD 事件风险。 130 091 英国生物银行参与者。分析仅限于具有可用外显子组测序数据的不相关的英国白人或爱尔兰参与者。基线时患有心血管疾病的参与者被排除在 CAD 事件分析之外。 结果 在 130 091 名个体中，68 416 名 (52.6%) 为女性，平均 (SD) 年龄为 56.7 (8.0) 岁。在该队列中，9.0% 符合严重高胆固醇血症标准。 LDL-C 介于 210 至 229 mg/dL 和 LDL-C ≥230 mg/dL 的参与者相对于 LDL-C 介于 190 至 209 mg/dL 的参与者，CAD 风险略有增加（210–229 mg/dL：风险比 [HR]，1.3 [95% CI，1.1–1.7]；≥230 mg/dL：HR， 1.3 [95% CI，1.0–1.7]）。相反，当按遗传亚型对风险进行分层时，相对于非遗传性高胆固醇血症亚型，单基因家族性高胆固醇血症、升高的 Lp(a) 和二次高胆固醇血症亚型的 CAD 发病率增加（单基因家族性高胆固醇血症：HR，2.3 [95% CI，1.4–4.0]；升高的 Lp(a)：HR，1.5 [95% CI， 1.2-2.0]；两次命中：HR，1.9 [95% CI，1.4-2.6]），而多基因高胆固醇血症则不然。 结论 对于严重高胆固醇血症患者，基于遗传学的单基因家族性高胆固醇血症亚型和 Lp(a) 提供了比基于 LDL-C 的分层更好的 10 年 CAD 风险分层。
BACKGROUNDSevere hypercholesterolemia, defined as LDL (low-density lipoprotein) cholesterol (LDL-C) measurement ≥190 mg/dL, is associated with increased risk for coronary artery disease (CAD). Causes of severe hypercholesterolemia include monogenic familial hypercholesterolemia, polygenic hypercholesterolemia, elevated lipoprotein(a) [Lp(a)] hypercholesteremia, polygenic hypercholesterolemia with elevated Lp(a) (two-hit), or nongenetic hypercholesterolemia. The added value of using a genetics approach to stratifying risk of incident CAD among those with severe hypercholesterolemia versus using LDL-C levels alone for risk stratification is not known.METHODSTo determine whether risk stratification by genetic cause provided better 10-year incident CAD risk stratification than LDL-C level, a retrospective cohort study comparing incident CAD risk among severe hypercholesterolemia subtypes (genetic and nongenetic causes) was performed among 130 091 UK Biobank participants. Analyses were limited to unrelated, White British or Irish participants with available exome sequencing data. Participants with cardiovascular disease at baseline were excluded from analyses of incident CAD.RESULTSOf 130 091 individuals, 68 416 (52.6%) were women, and the mean (SD) age was 56.7 (8.0) years. Of the cohort, 9.0% met severe hypercholesterolemia criteria. Participants with LDL-C between 210 and 229 mg/dL and LDL-C ≥230 mg/dL showed modest increases in incident CAD risk relative to those with LDL-C between 190 and 209 mg/dL (210–229 mg/dL: hazard ratio [HR], 1.3 [95% CI, 1.1–1.7]; ≥230 mg/dL: HR, 1.3 [95% CI, 1.0–1.7]). In contrast, when risk was stratified by genetic subtype, monogenic familial hypercholesterolemia, elevated Lp(a), and two-hit hypercholesterolemia subtypes had increased rates of incident CAD relative to the nongenetic hypercholesterolemia subtype (monogenic familial hypercholesterolemia: HR, 2.3 [95% CI, 1.4–4.0]; elevated Lp(a): HR, 1.5 [95% CI, 1.2–2.0]; two-hit: HR, 1.9 [95% CI, 1.4–2.6]), while polygenic hypercholesterolemia did not.CONCLUSIONSGenetics-based subtyping for monogenic familial hypercholesterolemia and Lp(a) in those with severe hypercholesterolemia provided better stratification of 10-year incident CAD risk than LDL-C-based stratification.