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 StudyKamstrup PR, Hung M-Y, Witztum JL, et al. - Arterioscler Thromb Vasc Biol. 2017, in press. https://doi.org/10.1161/ATVBAHA.116.308761
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.