Genetic Evidence That Lipoprotein(a) Associates With Atherosclerotic Stenosis Rather Than Venous Thrombosis

Abstract

Objective— The aim of the present study was to determine whether lipoprotein(a) [Lp(a)], considered a causal risk factor for cardiovascular disease, primarily promotes thrombosis or atherosclerosis. Methods and Results— Using a Mendelian randomization study design, we measured plasma Lp(a) and genetically elevated Lp(a) levels through the LPA kringle IV type 2 repeat genotype in 41231 individuals. We included 2 general population studies of both venous thrombosis and combined thrombosis and atherosclerosis in coronary arteries (=myocardial infarction), and 3 ­case–­control studies of atherosclerotic stenosis. Neither Lp(a) tertiles nor LPA kringle IV type 2 tertiles associated with the risk of venous thrombosis in general population studies (trend: P =0.12–0.76), but did each associate with risk of coronary, carotid, and femoral atherosclerotic stenosis in ­case–­control studies (trend: P <0.001 to 0.04). Lp(a) and LPA kringle IV type 2 tertiles also associated with the risk of myocardial infarction in general population studies (trend: P <0.001 to 0.003). For doubling of Lp(a) levels, instrumental variable estimates of hazard/odds ratios were 1.02 (95% CI 0.90–1.15) and 1.04 (0.93–1.16) for venous thrombosis in the 2 general population studies, 1.12 (1.01–1.25), 1.17 (1.05–1.32), and 1.16 (1.01–1.35), respectively, for coronary, carotid, and femoral atherosclerotic stenosis in ­case–control studies, and 1.21 (1.10–1.33) and 1.17 (1.05–1.29) for myocardial infarction in general population studies. Conclusion— This supports that Lp(a) primarily promotes atherosclerotic stenosis rather than venous thrombosis.