Department of Cardiovascular Medicine (B.A.S., O.D., M.S.S., I.J.K.), Mayo Clinic, Rochester, MN.
VA Palo Alto Health Care System, Palo Alto (S.L.C., C.T., X.Z., T.L.A.).
Circ Genom Precis Med. 2021 Aug;14(4):e003354. doi: 10.1161/CIRCGEN.120.003354. Epub 2021 Jul 20.
Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry.
We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization-phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants.
In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA-odds ratio and 95% CI for coronary heart disease 1.28 (1.16-1.41); cerebrovascular disease 1.14 (1.07-1.21); peripheral artery disease 1.22 (1.11-1.34); abdominal aortic aneurysm 1.28 (1.17-1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99-1.24) and cerebrovascular disease 1.06 (0.99-1.14) but similar for peripheral artery disease 1.16 (1.01-1.33) and abdominal aortic aneurysm 1.34 (1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10-1.62), mitral valve disorders 1.18 (1.09-1.27), congestive heart failure 1.12 (1.05-1.19), and chronic kidney disease 1.07 (1.01-1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94-1.25), mitral valve disorders 1.02 (0.89-1.16), congestive heart failure 1.02 (0.95-1.10), or chronic kidney disease 1.05 (0.99-1.12). Mendelian randomization-phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension.
Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.
脂蛋白(a)（Lp(a)）水平在非裔个体中高于欧洲裔个体。我们研究了遗传预测的 Lp(a)水平与（1）动脉粥样硬化性心血管疾病亚型：冠心病、脑血管疾病、外周动脉疾病和腹主动脉瘤，以及（2）按血统分层的非动脉粥样硬化性心血管疾病表型之间的关联。
我们分别在电子病历和基因组学、英国生物库和百万退伍军人计划队列中进行了（1）孟德尔随机化分析，用于先前报道的心血管关联，以及（2）孟德尔随机化-表型全基因组关联分析，用于新的关联。分析按血统在联合队列中分层，该队列包括 804507 名欧洲裔和 103580 名非裔个体。
在使用联合队列的孟德尔随机化分析中，Lp(a)水平每增加 1 个标准差，与动脉粥样硬化性心血管疾病亚型相关，在欧洲裔中，冠心病的比值比和 95%置信区间为 1.28（1.16-1.41）；脑血管疾病 1.14（1.07-1.21）；外周动脉疾病 1.22（1.11-1.34）；腹主动脉瘤 1.28（1.17-1.40）；而非裔个体中的效应估计值低于欧洲裔个体，且冠心病（1.11（0.99-1.24）和脑血管疾病（1.06（0.99-1.14））的相关性不显著，但外周动脉疾病（1.16（1.01-1.33））和腹主动脉瘤（1.34（1.11-1.62））的相关性相似。在欧洲裔个体中，Lp(a)水平每增加 1 个标准差，与主动脉瓣疾病（1.34（1.10-1.62））、二尖瓣疾病（1.18（1.09-1.27））、充血性心力衰竭（1.12（1.05-1.19））和慢性肾脏病（1.07（1.01-1.14））相关。而非裔个体中，主动脉瓣疾病（1.08（0.94-1.25））、二尖瓣疾病（1.02（0.89-1.16））、充血性心力衰竭（1.02（0.95-1.10））和慢性肾脏病（1.05（0.99-1.12））的相关性不显著。孟德尔随机化-表型全基因组关联分析在欧洲裔个体中确定了与动脉血栓栓塞性疾病、非主动脉瘤性疾病、心房颤动、心脏传导障碍和高血压相关的新的心血管关联。
在欧洲裔个体中，遗传上 Lp(a)水平升高与许多心血管疾病显著相关，但在非裔个体中并不显著。Lp(a)与欧洲裔个体的四大主要动脉床的动脉粥样硬化性心血管疾病相关，但仅与非裔个体的外周动脉疾病和腹主动脉瘤相关。此外，还在欧洲裔个体中检测到了新的心血管关联。
