Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study

Abstract

Lipoprotein(a) (Lp(a)) was fi rst described by Berg in 1963 ( 1 ). Lp(a) is a lipoprotein similar in structure to LDL, but differs from LDL in having apo(a), a large glycoprotein, attached to apoB-100 by a disulfi de bond ( 2 ). Apo(a) shares strong homology with several regions of plasminogen ( 3 ), including the protease domain, the kringle 5 domain, and 10 types of the kringle 4 domain. It has been shown that apo(a) is highly polymorphic in size due to different numbers of the kringle 4 type 2 (kringle-4 2 ) domain, ranging from a minimum of 3 to greater than 40 ( 4 ). Plasma levels of Lp(a) are highly heritable ( 2, 5 ) and are inversely correlated with the apo(a) isoform size, with subjects carrying small isoforms having high plasma Lp(a) levels ( 5 ). Metabolic studies have shown that the inverse association between plasma Lp(a) levels and apo(a) isoform size is due to differences in the hepatic secretion of apo(a), with subjects carrying small apo(a) isoforms having increased apo(a) secretion ( 6, 7 ). Boerwinkle et al. ( 8 ) indicated that 69% of the variability in plasma Lp(a) levels is accounted for by the number of apo(a) kringle-4 2 repeats, and an additional 21% of the variation is explained by other sequences within the gene coding for apo(a). Recently, the rs3798220 single-nucleotide polymorphism (SNP) in the apo(a) locus was found to be a strong predictor of Lp(a) levels and coronary heart disease (CHD) risk ( 9 ).Plasma Lp(a) levels are associated with CHD risk ( 10, 11 ). The mechanisms by which Lp(a) increases CHD risk are not well defi ned, but may include both a prothrombotic effect due to the similarity of apo(a) to the fi brinolytic pro-enzyme plasminogen ( 12, 13 ), and an atherogenic effect mediated by the preferential binding of oxidized phospholipids by Lp(a) as well as Lp(a) deposition in the arterial wall ( 14 ).Abstract The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile ( P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not signifi cantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a signifi cant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add signifi cant information about CHD risk. In addition, t...

Lipoprotein (a) measurements for clinical application

“…The turbidimetric assay as compared with results obtained by the reference ELISA method misclassifi ed 136 individuals as being at increased risk for CVD (false positive) and 23 individuals as being not at risk (false negative). All the false-positive results obtained by the turbidimetric assay were explained by overestimation of Lp(a) values based on the predominant apo(a) size in the sample ( 17 ). These fi ndings are consistent with the fact that the size of apo(a) in the calibrator was quite small and most samples in this population had apo(a) sizes larger than the apo(a) in the calibrator.…”

“…To directly evaluate the impact that method inaccuracy may have on the classifi cation of patients at high risk for CVD based on their Lp(a) levels, we used results of analyses performed on the Framingham offspring cohort during the fi fth cycle ( 17 ). Lp(a) levels and apo(a) isoforms were determined in our laboratory on 2,940 samples.…”

Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study

“…The authors also speculated that this inaccuracy might translate into inaccurate risk assessment. A direct comparison of three Lp(a) assays in a subset of the Framingham Offspring cohort demonstrated large interassay differences in Lp(a) values and consequently in the 80th percentile cutoff values, which was largely determined by differences in apo(a) isoform size ( 4 ). However, the number of coronary artery disease (CAD) events in that study was limited.…”

HDL-C, ABCA1-mediated cholesterol efflux, and lipoprotein(a): insights into a potential novel physiologic role of lipoprotein(a)

“…However, in that study, Lp(a)-C was assayed by Vertical Auto Profi le (VAP), a technology that may not accurately refl ect Lp(a) mass levels assayed by traditional immunoassays or accurate predictive value of cardiovascular risk ( 33 ). For example, Lp(a)-C measured by VAP, unlike Lp(a) mass, was not signifi cantly associated with cardiovascular risk after multivariate analysis in the Framingham Offspring Study ( 34 ). VAP resolves plasma lipoprotein species utilizing density gradient ultracentrifugation in a single tube spin, and given the signifi cant overlap between the densities of Lp(a) and HDL, the resolution of these two lipoproteins for downstream cholesterol measurement may be suboptimal.…”