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Report for Clinical Trial NCT02976818

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Relationships Between Lipoprotein(a) Levels and Aortic Valve Calcification in Patients With Heterozygous Familial Hypercholesterolemia

Aortic valve stenosis (AVS), the most common form of valve disease in the western world, afflicts more than 1 million individuals in North America [1] and the burden of AVS is high and is expected to double within the next 50 years [2]. Medical therapy to prevent development or reduce progression of AVS is currently not available and the only effective treatment for AVS is aortic valve replacement, for which costs have been estimated up to 120,000$ [3,4]. Recently, we and others have identified rs10455872 at the LPA locus as a susceptibility single nucleotide polymorphism (SNP) for aortic valve calcification (AVC) and AVS [5,6] and rs10455872 is associated with elevated plasma lipoprotein (Lp)(a) levels [7]. Lp(a) is a LDL-like particle consisting of hepatically synthesized apolipoprotein B-100 that is noncovalently bound to the plasminogen-like glycoprotein apolipoprotein(a) [8]. Lp(a) promotes atherosclerotic stenosis, and possibly thrombosis, and has been hypothesized to contribute to wound healing, each of which could explain an association with AVS [9,10]. Lp(a) is relatively refractory to both lifestyle and drug intervention, with only nicotinic acid and monoclonal antibody inhibition of the proprotein convertase subtilisin/kexin type 9 that have showed reductions in Lp(a) levels [11,12]. However, the evidence that patients with AVS could be characterized by high Lp(a) levels is scarce. Glader et al. [13] showed that plasma levels of Lp(a) were almost 1.5-fold higher in 101 patients with AVS compared to matched controls, although this relationship did not reach statistical significance. Subsequent studies have also reported an association between elevated plasma Lp(a) levels and higher prevalence of AVS. More specifically, Kamstrup and colleagues [14] reported that elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS in the general population with levels >90 mg/dL predicting a threefold increased risk. We have measured Lp(a) and oxidized phospholipids plasma levels in 220 patients with mild-to-moderate calcific AVS enrolled in the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial [15]. Results of this study suggest that high Lp(a) and oxidized phospholipids both predict calcific AVS progression, especially in younger patients with calcific AVS. We also found that statin therapy considerably increased both Lp(a) and oxidized phospholipids levels. Whether the fact that statins increase these risk factors for calcific AVS might explain at least to a certain extent why statins failed to promote calcific AVS regression or stabilization in at least four trials, including ASTRONOMER. Familial hypercholesterolemia (FH) is an autosomal codominant single-gene disorder caused by mutations in the LDL receptor gene that disrupt normal clearance of LDL. Phenotypic features characteristic of the disease's heterozygous form are 2- to 3-fold raise in plasma LDL-cholesterol concentrations, tendinous xanthomatosis and premature atherosclerotic coronary artery disease. High Lp(a) levels have been shown to explain residual cardiovascular disease risk in FH [16,17]. Recent studies have demonstrated that FH heterozygotes have elevated AVC compared with non-FH subjects [18] and that Lp(a) levels were positively correlated with AVC in asymptomatic FH heterozygotes [19]. Vongpromek et al. [19] demonstrated that plasma Lp(a) concentration is a independent risk factor for AVC in a cohort of 129 asymptomatic heterozygous FH patients aged between 40 and 69 years. In this study, AVC was significantly associated with plasma Lp(a) level, age, body mass index, blood pressure, duration of statin use, cholesterol-year score and coronary artery calcification (CAC) score.

NCT02976818 Heterozygous Familial Hypercholesterolemia
MeSH: Hypercholesterolemia Calcinosis Hyperlipoproteinemia Type II Aortic Valve Stenosis
HPO: Aortic valve stenosis Calcinosis Hypercholesterolemia Increased LDL cholesterol concentration


Primary Outcomes

Measure: Association between Lp(a) concentrations and aortic valve calcification

Time: Week 1

Time Perspective: Cross-Sectional

Case-Control


There is one SNP

SNPs


1 rs10455872

Recently, we and others have identified rs10455872 at the LPA locus as a susceptibility single nucleotide polymorphism (SNP) for aortic valve calcification (AVC) and AVS [5,6] and rs10455872 is associated with elevated plasma lipoprotein (Lp)(a) levels [7].



HPO Nodes


HPO:
Aortic valve stenosis
Genes 65
ESCO2 ADAMTS10 KRAS SLC2A10 LDLRAP1 IFIH1 SNIP1 FLI1 GJA1 CRELD1 MLXIPL LIMK1 FBLN5 B4GALT7 ANKS6 AMER1 NPHP3 FBN1 CCDC22 GTF2I VWF GLB1 LMNA DDX58 CLIP2 WASHC5 ARHGAP31 NEK8 SCN1B CYP24A1 EBP ACTB GATA4 WT1 GATA6 EHMT1 BAZ1B B3GALT6 NKX2-5 HAAO TAB2 APOB FGFR1 LTBP2 GATA5 ELN GNPTG RFC2 BCOR GTF2IRD1 IDUA CBL LDLR TBL2 ABCG5 ABCG8 NR2F2 NOTCH1 NOTCH2 FOXF1 ADAMTSL2 PCSK9 SMAD4 SMAD6 CHST3
Calcinosis
Genes 9
LMNA GEMIN4 SAMD9 GNAS LBR AGXT ZMPSTE24 CASR GALNT3
Hypercholesterolemia
Genes 39
GHR LDLRAP1 PHKA2 FLII PYGL APOB LIPA OCRL SETX APOC3 CAV1 DEAF1 CAV3 APOE CCDC115 TDP1 SLC7A7 LMNA NUP107 RSPO1 TTPA CYP7A1 LDLR PIK3R5 CETP COG4 ABCG5 ABCG8 SLC25A13 JAG1 DGAT1 RAI1 APTX IQSEC2 CYP27A1 PCSK9 CEP19 DYRK1B TMEM199
Increased LDL cholesterol concentration
Genes 22
SLC7A7 LMNA FHL1 LDLRAP1 TTPA CYP7A1 LDLR ABCG5 SMPD1 ABCG8 SYNE1 APOB TMEM43 LPL SYNE2 PCSK9 CEP19 EMD LCAT APOE CCDC115 TMEM199