Novel method for quantification of lipoprotein(a)-cholesterol: implications for improving accuracy of LDL-C measurements

Current methods for determining “LDL-C” in clinical practice measure the cholesterol content of both LDL and lipoprotein(a) [Lp(a)-C]. We developed a high-throughput, sensitive, and rapid method to quantitate Lp(a)-C and improve the accuracy of LDL-C by subtracting for Lp(a)-C (LDL-Ccorr). Lp(a)-C is determined following isolation of the Lp(a) on magnetic beads linked to monoclonal antibody LPA4 recognizing apolipoprotein(a). This Lp(a)-C assay does not detect cholesterol in plasma samples lacking Lp(a) and is linear up to 747 nM Lp(a). To validate this method clinically over a wide range of Lp(a) (9.0–822.8 nM), Lp(a)-C and LDL-Ccorr were determined in 21 participants receiving an Lp(a)-specific lowering antisense oligonucleotide and in eight participants receiving placebo at baseline, at 13 weeks during peak drug effect, and off drug. In the groups combined, Lp(a)-C ranged from 0.6 to 35.0 mg/dl and correlated with Lp(a) molar concentration (r = 0.76; P < 0.001). However, the percent Lp(a)-C relative to Lp(a) mass varied from 5.8% to 57.3%. Baseline LDL-Ccorr was lower than LDL-C [mean (SD), 102.2 (31.8) vs. 119.2 (32.4) mg/dl; P < 0.001] and did not correlate with Lp(a)-C. It was demonstrated that three commercially available “direct LDL-C” assays also include measures of Lp(a)-C. In conclusion, we have developed a novel and sensitive method to quantitate Lp(a)-C that provides insights into the Lp(a) mass/cholesterol relationship and may be used to more accurately report LDL-C and reassess its role in clinical medicine.