Lipoprotein(a) is causally associated with calcific aortic valve disease (CAVD). Lipoprotein(a) carries proinflammatory and procalcific oxidized phospholipids (OxPL). We tested whether the CAVD risk is mediated by the content of OxPL on lipoprotein(a).Approach and Results—
A case–control study was performed within the Copenhagen General Population Study (n=87 980), including 725 CAVD cases (1977–2013) and 1413 controls free of cardiovascular disease. OxPL carried by apoB (apolipoprotein B-100; OxPL-apoB) or apolipoprotein(a) (OxPL-apo(a)) containing lipoproteins, lipoprotein(a) levels, LPA kringle IV type 2 repeat, and rs10455872 genetic variants were measured. OxPL-apoB and OxPL-apo(a) levels correlated with lipoprotein(a) levels among cases (r=0.75 and r=0.95; both P<0.001) and controls (r=0.65 and r=0.93; both P<0.001). OxPL-apoB levels associated with risk of CAVD with odds ratios of 1.2 (95% confidence interval [CI]:1.0–1.6) for 34th to 66th percentile levels, 1.6 (95% CI, 1.2–2.1) for 67th to 90th percentile levels, 2.0 (95% CI, 1.3–3.0) for 91st to 95th percentile levels, and 3.4 (95% CI, 2.1–5.5) for levels >95th percentile, versus levels <34th percentile (trend, P<0.001). Corresponding odds ratios for OxPL-apo(a) were 1.2 (95% CI, 1.0–1.5), 1.2(95% CI, 0.9–1.6), 2.1(95% CI, 1.4–3.1), and 2.9(95% CI, 1.9–4.5; trend, P<0.001) and were similar for lipoprotein(a). LPA genotypes associated with OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels and explained 34%, 46%, and 39%, respectively, of the total variation in levels. LPA genotypes associated with risk of CAVD; a doubling in genetically determined OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels associated with odds ratio of CAVD of 1.18 (95% CI, 1.10–1.27), 1.09 (95% CI, 1.05–1.13), and 1.09 (95% CI, 1.05–1.14), respectively, comparable to the corresponding observational estimates of 1.27 (95% CI, 1.16–1.39), 1.13 (95% CI, 1.08–1.18), and 1.11 (95% CI, 1.06–1.17).Conclusions—
OxPL-apoB and OxPL-apo(a) are novel genetic and potentially causal risk factors for CAVD and may explain the association of lipoprotein(a) with CAVD.