Physicians' Academy for Cardiovascular Education

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

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

Background

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 [6].

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).

Main results

Conclusion

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.

References

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