Autism and Developmental Medicine Institute Geisinger, Lewisburg, PA (A.S.F.B., M.T.O.).
Department of Genomic Health, Geisinger, Danville, PA (L.K.J., S.S.G.).
Arterioscler Thromb Vasc Biol. 2023 Oct;43(10):2058-2067. doi: 10.1161/ATVBAHA.123.319341. Epub 2023 Aug 17.
Severe 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.
To 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.
Of 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.
Genetics-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.
重度高胆固醇血症定义为 LDL（低密度脂蛋白）胆固醇（LDL-C）测量值≥190mg/dL，与冠状动脉疾病（CAD）风险增加相关。重度高胆固醇血症的病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)]升高性高胆固醇血症、多基因高胆固醇血症伴 Lp(a)升高（双打击）或非遗传性高胆固醇血症。与单独使用 LDL-C 水平进行风险分层相比，使用遗传学方法对重度高胆固醇血症患者发生 CAD 的风险进行分层的附加值尚不清楚。
为了确定遗传病因分层是否比 LDL-C 水平提供更好的 10 年 CAD 事件风险分层，对英国生物库中 130091 名参与者进行了一项回顾性队列研究，比较了重度高胆固醇血症亚组（遗传和非遗传病因）的 CAD 事件风险。分析仅限于具有可用外显子组测序数据的无血缘关系的白种英国或爱尔兰参与者。从 CAD 事件风险分析中排除了基线时患有心血管疾病的参与者。
在 130091 名参与者中，68416 名（52.6%）为女性，平均（SD）年龄为 56.7（8.0）岁。队列中有 9.0%的人符合重度高胆固醇血症标准。与 LDL-C 在 190-209mg/dL 之间的参与者相比，LDL-C 在 210-229mg/dL 和 LDL-C≥230mg/dL 的参与者 CAD 事件风险适度增加（210-229mg/dL：风险比[HR]，1.3[95%CI，1.1-1.7]；≥230mg/dL：HR，1.3[95%CI，1.0-1.7]）。相比之下，当根据遗传亚型分层风险时，与非遗传性高胆固醇血症亚型相比，单基因家族性高胆固醇血症、Lp(a)升高和双打击高胆固醇血症亚型的 CAD 事件发生率更高（单基因家族性高胆固醇血症：HR，2.3[95%CI，1.4-4.0]；Lp(a)升高：HR，1.5[95%CI，1.2-2.0]；双打击：HR，1.9[95%CI，1.4-2.6]），而多基因高胆固醇血症则没有。
对于重度高胆固醇血症患者，基于遗传学的单基因家族性高胆固醇血症和 Lp(a)亚型分类比基于 LDL-C 的分类能更好地分层 10 年 CAD 事件风险。
