Relationship Between LDL-Cholesterol, Small and Dense LDL Particles, and mRNA Expression in a Cohort of African Americans.

Abstract

Understanding the characteristics and behavior of LDL particles provides insights into the atherogenic risk of high levels of LDL cholesterol (LDL-C) in hypercholesterolemia. Studying LDL particles helps identify specific LDL subtypes (e.g., small and dense LDL particles, sdLDL) that may be atherogenic and, consequently, potential targets for therapeutics. This study cohort consists of African Americans (AAs), a population disproportionately affected by hypercholesterolemia, thereby accentuating the importance of the investigation.Differential expression (DE) analysis was undertaken utilizing a dataset comprising 17,947 protein-coding mRNAs from the whole-blood transcriptomes of 416 samples to identify mRNAs associated with LDL-C and sdLDL. Subsequently, mediation analyses were used to investigate the mediating role of sdLDL particles on the relationship between LDL-C and mRNA expression. Finally, pathway enrichment analysis was conducted to identify pathways involving mRNAs whose relationship with LDL-C is mediated by sdLDL.DE analysis revealed 1048 and 284 mRNA transcripts differentially expressed by LDL-C and sdLDL, respectively. Mediation analysis revealed that the associations between LDL-C and 33 mRNAs were mediated by sdLDL. Pathway analysis showed the 33 mRNAs are involved in pathways associated with immune system, inflammatory response, metabolism, and cardiovascular disease (CVD) risk.Our study provides valuable insights into the complex interplay between LDL-C, sdLDL and mRNA expression in a large sample of AAs. The results underscore the importance of incorporating sdLDL measurement alongside LDL-C levels to improve the accuracy of managing hypercholesterolemia and effectively stratify the risk of CVD. This is essential as differences in sdLDL modulate atherogenic properties at the transcriptome level.