From the Department of Clinical Biochemistry, Rigshospitalet (A.B.W., A.T.-H.), Department of Clinical Biochemistry, Herlev and Gentofte Hospital (B.G.N.), and Copenhagen City Heart Study, Frederiksberg Hospital (B.G.N., A.T.-H.), Copenhagen University Hospital, University of Copenhagen, Denmark; Department of Clinical Biochemistry, Zealand University Hospital, Denmark (A.B.W.); and Copenhagen General Population Study, Herlev and Gentofte Hospital, Denmark (B.G.N., A.T.-H.).
Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):660-668. doi: 10.1161/ATVBAHA.117.310473. Epub 2018 Jan 18.
Loss-of-function mutations in associate with low remnant cholesterol levels and low risk of ischemic vascular disease (IVD). Because some studies show an additional association with low levels of low-density lipoprotein cholesterol (LDL-C), low LDL-C may explain the low risk of IVD in loss-of-function heterozygotes. We tested to what extent the low risk of IVD in loss-of-function heterozygotes is mediated by low plasma remnant cholesterol and LDL-C.
In loss-of-function heterozygotes versus noncarriers, we first determined remnant cholesterol and LDL-C levels in meta-analyses of 137 895 individuals. Second, we determined whether the association with LDL-C was masked by lipid-lowering therapy. Finally, using mediation analysis, we determined the fraction of the low risk of IVD and ischemic heart disease mediated by remnant cholesterol and LDL-C. In meta-analyses, remnant cholesterol was 43% lower (95% confidence interval, 40%-47%), and LDL-C was 4% lower (1%-6%) in loss-of-function heterozygotes (n=776) versus noncarriers. In the general population, LDL-C was 3% lower in loss-of-function heterozygotes versus noncarriers, 4% lower when correcting for lipid-lowering therapy, and 3% lower in untreated individuals ( values, 0.06-0.008). Remnant cholesterol mediated 37% of the observed 41% lower risk of IVD and 54% of the observed 36% lower risk of ischemic heart disease; corresponding values mediated by LDL-C were 1% and 2%.
The low risk of IVD observed in loss-of-function heterozygotes is mainly mediated by the associated low remnant cholesterol and not by low LDL-C. Furthermore, the contribution of LDL-C to IVD risk was not masked by lipid-lowering therapy. This suggests and remnant cholesterol as important new targets for reducing cardiovascular risk.
与低残余胆固醇水平和缺血性血管疾病（IVD）风险低相关的 功能丧失突变。由于一些研究显示与低密度脂蛋白胆固醇（LDL-C）水平降低有关，因此低 LDL-C 可能解释了 功能丧失杂合子中 IVD 风险低的原因。我们测试了 功能丧失杂合子中 IVD 风险低在多大程度上是由低血浆残余胆固醇和 LDL-C 介导的。
在 功能丧失杂合子与非携带者中，我们首先在 137895 人的荟萃分析中确定了残余胆固醇和 LDL-C 水平。其次，我们确定了降脂治疗是否掩盖了与 LDL-C 的关联。最后，使用中介分析确定了残余胆固醇和 LDL-C 介导的 IVD 和缺血性心脏病风险降低的比例。在荟萃分析中，与非携带者相比，残余胆固醇降低了 43%（95%置信区间，40%-47%），LDL-C 降低了 4%（1%-6%）（n=776）。在一般人群中，与非携带者相比， 功能丧失杂合子的 LDL-C 降低了 3%，纠正降脂治疗后降低了 4%，未治疗个体降低了 3%（ 值，0.06-0.008）。残余胆固醇介导了观察到的 41%的 IVD 风险降低的 37%，以及观察到的 36%的缺血性心脏病风险降低的 54%；LDL-C 介导的相应值分别为 1%和 2%。
在 功能丧失杂合子中观察到的 IVD 风险低主要是由相关的低残余胆固醇介导的，而不是由低 LDL-C 介导的。此外，降脂治疗并未掩盖 LDL-C 对 IVD 风险的贡献。这表明 和残余胆固醇是降低心血管风险的重要新靶点。
