Deficiency of the Lipoprotein Lipase Pathway Modifies the Phenotypic Expression of Genetically Determined...

Plasma lipoprotein(a) [Lp(a)] concentrations are primarily genetically determined, but whether disruption of triglyceride-rich lipoprotein metabolism modifies Lp(a) expression is unknown. Familial chylomicronemia syndrome (FCS) provides a human model to investigate this relationship. In the phase 3 Balance trial, 66 participants with genetically confirmed FCS (triglycerides ≥880 mg/dL) underwent Lp(a) measurement, apo(a) isoform phenotyping, and measurement of OxPL-apo(a) and OxPL-apoB. Results were compared with 66 age- and sex-matched participants with moderate hypertriglyceridemia from Essence-TIMI 73b. Median Lp(a) concentrations were similar (9.77[4.64-33.6] vs 11.8[5.23-90.4] nmol/L; P=0.148), but the Lp(a) distribution in FCS was shifted downward, driven by fewer individuals with high Lp(a) concentrations despite similar apo(a) isoform distributions. The inverse relationship between apo(a) isoform size and Lp(a) was preserved (P for trend <0.001), with lower Lp(a) in FCS after stratification by apo(a) isoform size (P=0.006). Median [IQR] Lp(a) was lower in FCS with <17 KIV repeats (67.4 [49.2-93.7] vs 175 [145-324] nmol/L; P=0.018) and 17-20 KIV repeats (23.9 [9.37-55.3] vs 138 [17.1-192] nmol/L; P=0.012). OxPL-apo(a) and OxPL-apoB were lower in FCS (P=0.026 and P<0.0001, respectively). The OxPL-apo(a)/OxPL-apoB ratio was approximately 70% lower (0.60 [0.27-1.69] vs 2.05 [1.49-2.79]; P<0.0001) and showed a pronounced inverse trend across apo(a) isoform size in FCS (P<0.001), consistent with altered relative OxPL carriage among apoB-containing lipoproteins. Olezarsen had no consistent effects on Lp(a) or OxPL biomarkers. These findings demonstrate that functional deficiency of the LPL pathway modifies the phenotypic expression of genetically determined Lp(a) and alters OxPL distribution among apoB-containing lipoproteins.