Introduction: An elevated level of lipoprotein(a) [Lp(a)] is an independent causal risk factor for cardiovascular disease. Non-genetic factors do not appreciably influence Lp(a) levels due to a strong genetic control. However, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to reduce Lp(a) levels. The association of PCSK9 with Lp(a) level and its major genetic determinant—apolipoprotein(a) [apo(a)] size—is not fully understood. In this study, we assessed the relationship between PCSK9, Lp(a) level, apo(a) size, age, and race/ethnicity.
Methods: Healthy Caucasian and African-American families were recruited from the general population (age range: 6–74 years, N=267). PCSK9 and Lp(a) levels were assayed enzymatically; apo(a) isoform and LPA allele sizes and isoform-specific Lp(a) levels were determined.
Results: In all participants, PCSK9 levels differed significantly by race/ethnicity, age, and sex. Thus, the mean PCSK9 levels were significantly higher in African-Americans vs. Caucasians (104 ± 29 vs. 95 ± 30 ng/mL, respectively, p=0.020), in adults vs. children (102 ± 29 vs. 92 ± 31 ng/mL, respectively, p=0.001) and in females vs. males (103 ± 30 vs. 94 ± 29 ng/mL, respectively, p=0.007). PCSK9 levels were not associated with total plasma Lp(a) levels neither in all participants nor in ethnicity-specific analyses. However, PCSK9 levels were significantly and positively associated with isoform-specific Lp(a) levels carried by the larger apo(a) size in all subjects (r=0.139, p=0.0361). In race/ethnicity analyses, a significant association was seen for African-Americans (r=0.268, p=0.0199), but not for Caucasians. In contrast, there were no significant associations of PCSK9 with isoform-specific Lp(a) levels for the smaller apo(a) sizes in all participants nor in ethnic-specific analyses. Of note, PCSK9 levels were significantly negatively associated with the larger apo(a) isoform sizes in all participants (r=-0.139, p=0.0366). Although significant in both groups, heritability of PCSK9 level was higher in Caucasians than in African-Americans (47% vs. 22%, respectively).
Conclusions: Among African-Americans, but not Caucasians, PCSK9 levels were associated with isoform-specific Lp(a) levels carried on larger, but not smaller, apo(a) sizes. The findings illustrate a diverging relationship of PCSK9 with isoform-specific Lp(a) levels.