Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada.
Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.
J Am Coll Cardiol. 2020 Jun 2;75(21):2682-2693. doi: 10.1016/j.jacc.2020.03.065.
Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why.
This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically.
We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486).
Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH.
These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.
脂蛋白(a)是一种致动脉粥样硬化的低密度脂蛋白样颗粒，其循环水平在很大程度上由遗传决定。家族性高胆固醇血症（FH）患者的脂蛋白(a)水平升高；然而，目前尚不清楚原因。
本研究比较了临床确诊 FH 患者（FH 队列，n=391）和人群中基因诊断 FH 患者（英国生物库；n=37486）的脂蛋白(a)水平和相关遗传因素。
我们研究了临床诊断为 FH 的个体（FH 队列，n=391）和人群中基因诊断为 FH 的个体（英国生物库；n=37486）中升高的脂蛋白(a)的原因。
FH 队列患者的脂蛋白(a)水平明显高于一般人群或非 FH 血脂异常患者。这归因于 rs10455872-G LPA 风险等位基因的频率增加（15.1% vs. 8.8%；p<0.05）。然而，在 FH 队列中，脂蛋白(a)水平不因 FH 致病变异的存在与否而有所不同（平均值=1.43 log mg/dl vs. 1.42 log mg/dl；p=0.97）。英国生物库队列中，脂蛋白(a)水平在有和无 FH 致病变异的个体之间也没有统计学差异，该队列代表不受心血管确定偏倚的人群样本（n=221 vs. 37486）。我们进行了一项脂蛋白(a)基因型与 19202 种表型的全基因组关联研究，证明脂蛋白(a)升高与低密度脂蛋白胆固醇升高、心血管疾病家族史、早发冠心病和 FH 诊断有关。
这些结果表明，FH 不会导致脂蛋白(a)升高，但脂蛋白(a)升高会增加个体具有遗传 FH 并被临床识别的可能性。
