Abstract 484: Apolipoprotein (a) Isoform Size Regulates Both the Production and Clearance of Circulating Lipoprotein (a)

Introduction: Lipoprotein (a) [Lp(a)] is a cardiovascular risk factor. Plasma levels of Lp(a) have been estimated to be 90% genetically determined, with the number of the Kringle IV Type 2 (KVI2) repeats being most important. The inverse relationship between plasma Lp(a) levels and isoform size has been established in large cohorts. The effects of apo(a) isoform size on the fractional clearance rate (FCR) and production rate (PR) of Lp(a) have been less well studied, although early reports indicated that isoform size was related mainly to the PR of apo(a). Methods: We measured Lp(a) levels, isoform size (KIV repeats), and the relative expression of each isoform in 41 healthy volunteers. An “effective allele size” was calculated in each subject using the relative expression (by agarose gel electrophoresis) of each isoform. Stable isotope studies were performed in all subjects, using D 3 -leucine, to determine FCR and PR of apo(a). Results: As found in larger cohorts, plasma Lp(a) levels were inversely correlated with isoform size (R=-0.52, p=.0005), Fig1A. In the entire cohort, Lp(a) levels had a modest negative correlation with PR (R=-0.33, P=0.04), Fig1B, and no correlation with FCR. The relationship of effective isoform size with PR was similar for subgroups with small (<23, N=20) and large (>23, N=21) effective isoform sizes. However, FCR showed a significant relationship (R=0.64, p=0.003), Fig1C,only for the subgroup with effective isoform sizes < 23; there was no relationship in individuals with effective isoform sizes >23. Our results show that the inverse relationship of Lp(a) levels with effective allele size is due to a decrease in PR with increasing effective allele size, and, importantly, an increase in FCR up to an effective allele size of 23. Conclusion: Our studies indicate that apo(a) allele size is an important regulator of both the production and clearance of Lp(a).