Available online 10 August 2025

High plasma Lp(a) levels are associated with increased IFN-γ-associated gene expression in human classical monocytes.

Plasma CXCL10 concentrations are significantly elevated in individuals with high Lp(a) without ASCVD.

Chromatin accessibility is not significantly altered by elevated plasma Lp(a) levels or the presence of ASCVD in human circulating classical monocytes

: High plasma lipoprotein(a) [Lp(a)] levels are associated with accelerated atherosclerosis and subsequent atherosclerotic cardiovascular disease (ASCVD), potentially through enhanced inflammatory signaling of monocytes. Given that monocytes are major players in ASCVD risk and the role of epigenetic changes in regulating their responsiveness, we propose that investigating changes in chromatin accessibility could reveal the underlying mechanisms of enhanced monocyte inflammation.

: In this observational case-control study, we collected blood from subjects with low (<25nmol/L) and elevated (>350nmol/L) plasma Lp(a) with and without a history of ASCVD, matched for age and sex. A total of 60 subjects were included in the study, comprising 60% males and a mean age of 62.8±7.8 years. We assessed gene expression and chromatin accessibility of FACS-sorted classical monocytes using RT-qPCR and bulk ATAC-sequencing and analyzed plasma cytokine levels.

: Subjects with high plasma Lp(a) showed significantly increased gene expression of IFIT3, along with a trend for IFIT2 and CXCL10. At the plasma level, subjects with high Lp(a) without ASCVD were distinguished by higher concentrations of CXCL10. While these results are consistent with previous research demonstrating increased IFN-γ signaling in monocytes of individuals with elevated Lp(a), we did not detect differences in chromatin accessibility of monocytes between subjects with high or low Lp(a), irrespective of ASCVD status.

: While subjects with high Lp(a) levels showed enhanced monocyte inflammation, no differences in chromatin accessibility were detected. This suggests that the pro-inflammatory signature of Lp(a) and ASCVD on monocytes is regulated at a level other than chromatin accessibility.

Lipoprotein(a)

atherosclerotic cardiovascular disease

monocyte

epigenetic

chromatin

ATAC-sequencing

© 2025 Published by Elsevier Inc. on behalf of National Lipid Association.