Relationship of apolipoprotein(a) isoform size with clearance and production of lipoprotein(a) in a diverse cohort

Lipoprotein(a) Lp(a) has two main proteins, apoB100 and apo(a). High levels of Lp(a) confer an increased risk for atherosclerotic cardiovascular disease. Most people have two circulating isoforms of apo(a) differing in their molecular mass, determined by the number of Kringle IV Type 2 repeats. Previous studies report a strong inverse relationship between Lp(a) levels and apo(a) isoform sizes. The roles of Lp(a) production and fractional clearance and how ancestry affects this relationship remain incompletely defined. We therefore examined the relationships of apo(a) size with Lp(a) levels and both apo(a) fractional clearance rates (FCR) and production rates (PR) in 32 individuals not on lipid-lowering treatment. We determined plasma Lp(a) levels and apo(a) isoform sizes, and used the relative expression of the two isoforms to calculate a “weighted isoform size” (wIS). Stable isotope studies were performed, using D3-leucine, to determine the apo(a) FCR and PR. As expected, plasma Lp(a) concentrations were inversely correlated with wIS (R2 = 0.27; P = 0.002). The wIS had a modest positive correlation with apo(a) FCR (R2 = 0.10, P = 0.08), and a negative correlation with apo(a) PR (R2 = 0.11; P = 0.06). The relationship between wIS and PR became significant when we controlled for self-reported race and ethnicity (SRRE) (R2 = 0.24, P = 0.03); controlling for SRRE did not affect the relationship between wIS and FCR. Apo(a) wIS plays a role in both FCR and PR; however, adjusting for SRRE strengthens the correlation between wIS and PR, suggesting an effect of ancestry.