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.


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


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.


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