Triglycerides and T Cells in Cardiovascular Risk: Inflammatory Transcriptomic Profile in Hypertriglyceridemia Patients' T Cells

Abstract

Triglycerides and T cells play a key role in atherosclerosis, the leading cause of cardiovascular disease (CVD). Moderately elevated triglycerides have emerged as a causal risk factor, and T cells are a prominent component of atherosclerotic plaques. This cross-sectional study examined transcriptomic differences in T cells among patients with varying triglyceride levels via RNA sequencing. We analyzed CD4⁺ and CD8⁺ T cells from 49 participants, including those with primary (genetic) and secondary moderate hypertriglyceridemia, severe hypertriglyceridemia, and hypotriglyceridemia. Patients with primary moderate hypertriglyceridemia exhibited a proinflammatory transcriptomic profile, including increased interleukin-6 receptor (IL6R) expression, which is implicated in CVD risk. Similar patterns appeared in CD8⁺ T cells and, to a lesser extent, in secondary moderate hypertriglyceridemia patients. Conversely, transcriptomic differences were reversed in hypotriglyceridemia and absent in severe hypertriglyceridemia patients. These findings suggest that elevated triglycerides may contribute to CVD by promoting a proinflammatory transcriptomic profile in T cells.

Keywords: T cells; atherosclerosis; hypertriglyceridemia; hypotriglyceridemia; transcriptomics; triglycerides.

Graphical abstract

Figure 1

Experimental Setup RNA sequencing was performed on isolated CD4⁺ and CD8⁺ T cells derived from participants with primary or secondary moderate hypertriglyceridemia, primary severe hypertriglyceridemia, hypotriglyceridemia, or control.

Figure 2

Differentially Expressed Genes in CD4⁺ and CD8⁺ T Cells From Primary and Secondary Moderate Groups as Compared With the Control Group (A) Dot plot of the raw count data for the gene IL6R in CD4⁺ T cells for the control, primary moderate, and secondary moderate groups. Dots are colored by cause of hypertriglyceridemia. (B) Differentially expressed genes in CD4⁺ and CD8⁺ T cells from primary and secondary moderate groups compared with the control group. Heatmap obtained from the DESeq2 analysis resulting in 42 differentially expressed genes (P_FDR < 0.050). Differentially expressed genes are clustered based on effect sizes. Bar on the right indicates the group in which the gene is differentially expressed (blue = CD4⁺ primary moderate, orange = CD8⁺ primary moderate, and green = CD8⁺ secondary moderate). Genes of interest are labelled, CD4⁺ T cells primary moderate n = 13, CD8⁺ T cells primary moderate n = 12, CD4⁺ T cells secondary moderate n = 14, and CD8⁺ T cells secondary moderate n = 9.

Figure 3

Differentially Expressed Genes in CD4⁺ and CD8⁺ T Cells From Primary Moderate, Secondary Moderate, Primary Severe, and Hypotriglyceridemia Groups as Compared With the Control Group Heatmap shows the expression of the aforementioned differentially expressed genes in the CD4⁺ and CD8⁺ T cells from primary severe hypertriglyceridemia and hypotriglyceridemia groups as well. Heatmap obtained from the DESeq2 analysis resulting in 42 differentially expressed genes (P_FDR < 0.050). Differentially expressed genes are clustered based on effect sizes. Genes of interest are labelled, CD4⁺ T cells primary moderate n = 13, CD8⁺ T cells primary moderate n = 12, CD4⁺ T cells secondary moderate n = 14, CD8⁺ T cells secondary moderate n = 9, CD4⁺ T cells primary severe n = 2, CD8⁺ T cells primary severe n = 2, CD4⁺ T cells hypotriglyceridemia n = 4, and CD8⁺ T cells hypotriglyceridemia n = 4.

Figure 4

Up- and Down-Regulated Pathways in Nonactivated CD8⁺ T cells Derived From Hypotriglyceridemia Patients (A) Pathway enrichment analysis of all upregulated CD8⁺ T-cell hypotriglyceridemia group differentially expressed genes generated using clusterProfiler using 10 human pathway databases. Top 10 enrichments are shown. (B) Pathway enrichment analysis of all down-regulated CD8⁺ T-cell hypotriglyceridemia group differentially expressed genes generated using clusterProfiler using 10 human pathway databases. Top 10 enrichments are shown.