OxPL on Lp(a) likely a genetic and probably also a causal risk factor for CAVD
Oxidized Phospholipids and Risk of Calcific Aortic Valve Disease - The Copenhagen General Population Study
Strong data, including those from Mendelian randomization studies, suggest that genetic variants in the LPA gene are associated with elevated lipoprotein(a), Lp(a) plasma levels and are a risk factor for calcific aortic valve disease (CAVD) [1-3]. As Lp(a) is the preferential lipoprotein carrier of phosphocholine-containing oxidized phospholipids (OxPL), it is hypothesized that the risk of Lp(a) in mediating CAVD may be affected by its OxPL content [4,5]. It has recently been shown that pre-existing coronary artery disease (CAD) patients with elevated OxPL on ApoB-100-containing lipoproteins (OxPL-ApoB), OxPL on Apo(a)-containing lipoproteins (OxPL-apo(a)) and Lp(a) levels have a much faster progression of CAVD and more frequent need for aortic valve replacement .
Therefore, the Copenhagen General Population Study (CGPS, n=2138 CAVD patients/2 matched cardiovascular disease-free controls per patients) investigated whether observationally as well as genetically elevated OxPL-ApoB (including Lp(a)) and OxPL-apo(a) levels are associated with increased risk of CAD. In this study, Mendelian randomization analyses were performed with 2 genetic LPA variants: the kringle IV type 2 repeat polymorphism (KIV-2), which determines the number of apo(a) kringle structures and the rs10455872 intron single nucleotide polymorphism (SNP).
- Concentrations of OxPL-apoB, OxPL-apo(a) and Lp(a) followed a similar distribution in controls and cases. In both patient groups, OxPL-apoB and lp(a) concentrations highly correlated (controls r=0.65, cases r=0.75, both P<0.001), as did OxPL-apo(a) and lp(a) concentration (controls r=0.93, cases r=0.95, P<0.001).
- Each nmol/L increase in OxPL-apoB was associated with a multivariable-adjusted OR for CAVD of 1.10 (95%CI: 1.07-1.14). Each 10 mg/dL increase in Lp(a) associated with a multivariable adjusted OR for CAVD of 1.10 (95%CI: 1.06-1.13).
- More specifically, the 34th to 66th, 67 to 90th, 91 to 95th and >95th percentile levels of OxPL-apoB were associated with a risk of CAVD with multivariable OR of 1.2 (95%CI: 1.0-1.6), 1.6 (95%CI: 1.2-2.1), 2.0 (95%CI: 1.3-3.0) and 3.4 (95% CI 2.1-5.5), respectively. These ORs 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), respectively (P trend <0.001) and for Lp(a) 1.1 (95%CI: 0.9-1.4), 1.2 (95%CI: 0.9-1.6), 2.0 (95%CI: 1.3-3.0) and 3.5 (95%CI: 2.2-5.6), respectively (P trend < 0.001).
- When additionally adjusted for lipid-lowering therapy, risk estimates for Lp(a), OxPL-apoB and OxPL-apo(a), results remained statistically significant although attenuated.
- A low number of LPA KIV-2 repeats and minor allele carrier status for LPA rs10455872 were associated with high levels of OxPL-apoB and OxPL-apo(a), as well as with elevated Lp(a) levels (all P<0.001): 1-5, 6-10, 11-33, 34-66 and 67-100 KIV-2 repeats had median Lp(a) levels of 70 (49-108), 58 (35-74), 22(7-55), 8(3-21) and 5(2-11) mg/dL respectively, which was 59 (44-75) and 7(3-16) mg/dL for carriers respectively non-carriers of the LPA rs10455872 variant. Median OxPL-apoB levels for mentioned KIV-2 groups were 7.7(4.8-11.7), 5.2(3.6-7.7), 3.0(1.7-5.8), 2.0(1.3-3.3) and 1.7(1.2-2.5) nmol/L respectively and 5.9(4.2-8.1) and 1.9 (1.2-2.9) for carriers and non-carriers respectively.
- The LPA KIV-2 genotype explained 24% of and 35% of OxPL-apoB and OxPL-apo(a) level variation and 29% of Lp(a) variation. Corresponding percentages for the rs10455872 genotype were 26, 34 and 30% respectively.
- A doubling in genetically determined OxPL-apoB, OxPL-apo(a) and Lp(a) levels was associated with ORs 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. For observational estimates, these numbers were 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), respectively.
In the CGPS study, both OxPL-apoB and OxPL-apo(a) were genetically and observationally associated with CAVD risk, independent of all other measured risk factors for CAVD (except for Lp(a)). Moreover, OxPL-apoB, OxPL-apo(a) and Lp(a) levels closely correlated. This suggests that OxPL on lp(a) is a genetic and likely causal risk factor for CAVD, which offers opportunities for novel therapeutic approaches for CAVD.