Inflammation
Amsterdam UMC study finds high Lp(a) raises monocyte inflammation genes but not chromatin accessibility, pointing to a non-epigenetic mechanism (J Clin Lipidol 2025)
Original title: Human monocyte inflammation in patients with Lp(a) or atherosclerotic cardiovascular disease is not accompanied by changes in chromatin accessibility in circulating classical monocytes
In this case-control study, researchers compared 60 subjects (60% male, mean age 62.8 years) with low (below 25 nmol/L) versus elevated (above 350 nmol/L) plasma Lp(a), with and without a history of atherosclerotic cardiovascular disease (ASCVD), matched for age and sex. Using FACS-sorted classical monocytes, RT-qPCR, ATAC-sequencing and plasma cytokine profiling, subjects with high Lp(a) showed significantly increased gene expression of IFIT3, and those with high Lp(a) but no ASCVD had higher plasma CXCL10, consistent with prior evidence of heightened interferon-gamma signalling in Lp(a)-associated monocytes. However, no differences in chromatin accessibility were detected between high and low Lp(a) groups regardless of ASCVD status. The authors conclude the pro-inflammatory monocyte signature linked to Lp(a) and ASCVD is regulated at a level other than chromatin accessibility, narrowing where future mechanistic work should look.
Original abstract
Background And Aims: 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.
Methods: In this observational case-control study, we collected blood from subjects with low (<25 nmol/L) and elevated (>350 nmol/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 fluorescence-activated cell sorting (FACS)-sorted classical monocytes using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and bulk assay for transposase-accessible chromatin (ATAC)-sequencing and analyzed plasma cytokine levels.
Results: Subjects with high plasma Lp(a) showed significantly increased gene expression of IFIT3. At the plasma level, subjects with high Lp(a) without ASCVD were distinguished by higher concentrations of chemokine C-X-C motif ligand 10 (CXCL10). While these results are consistent with previous research demonstrating increased interferon-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.
Conclusion: 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.
Dutch researchinflammationmechanisms
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.