Associations Between Plasma Lipoprotein(a) Levels and Circulating Monocyte Subsets Differ across Populations

OBJECTIVE: Lipoprotein(a) [Lp(a)] is a causal cardiovascular disease (CVD) risk factor, with plasma concentrations generally higher in Black than White individuals. Evidence suggests that elevated Lp(a), partly through oxidized phospholipid (oxPL)-mediated signaling, promotes a pro-inflammatory monocyte phenotype that may contribute to arterial inflammation and CVD. We examined associations between Lp(a) levels, apo(a) isoform size, and circulating monocyte populations in Black and White individuals using single-cell RNA sequencing (scRNA-seq). APPROACH AND RESULTS: Plasma Lp(a), apo(a) isoform size, inflammatory markers, and oxPL were measured using standardized assays in stored samples from a previously characterized cohort of 128 participants. After excluding smokers and individuals with type 2 diabetes, 34 participants remained (20 Black, 14 White). Participants were stratified into normal Lp(a) (median 12.6 nmol/L; n=15, 8 Black) and high Lp(a) (median 159 nmol/L; n=19, 12 Black) groups. Multivariable linear regression assessed associations between plasma Lp(a), Lp(a)-bound oxPL, and monocyte subset proportions. scRNA-seq identified six classical monocyte subsets, one non-classical monocyte subset, one MHCIIhi monocyte subset, and one interferon-responsive monocyte subset. Monocyte subset distributions did not differ between normal and high Lp(a) groups. However, race modified the association between plasma Lp(a) levels and non-classical monocyte abundance (P_interaction=0.032), with an inverse association observed in White participants (P=0.028) but not Black participants (P=0.470). OxPL bound to apo(a) correlated strongly with plasma Lp(a) concentrations (R2=0.84, P=3.3x10^1) and showed a race-dependent association with non-classical monocytes (P_interaction=0.014). Race also modified the association between plasma Lp(a) levels and classical 2 monocytes (P_interaction=0.027). CONCLUSIONS: These findings suggest that associations between Lp(a), oxPL, and circulating monocyte subsets differ by race and highlight the importance of considering self-reported race in studies of Lp(a)-related immune and cardiovascular phenotypes.