Profiling of immune‐related gene expression in children with familial hypercholesterolaemia

Abstract

Background Innate and adaptive immune responses are pivotal in atherosclerosis, but their association with early‐stage atherosclerosis in humans is incompletely understood. In this regard, untreated children with familial hypercholesterolaemia may serve as a human model to investigate the effect of elevated low‐density lipoprotein (LDL)‐cholesterol. Objectives We aimed to study the immunological and inflammatory pathways involved in early atherosclerosis by examining mRNA molecules in peripheral blood mononuclear cells (PBMCs) from children with FH. Methods We analysed the level of 587 immune‐related mRNA molecules using state‐of‐the‐art Nanostring technology in PBMCs from children with (n = 30) and without (n = 21) FH, and from FH children before and after statin therapy (n = 10). Results 176 genes (30%) were differentially expressed between the FH and healthy children at P < 0.05. Compared to healthy children, the dysregulated pathways in FH children included the following: T cells (18/19); B cells (5/6); tumour necrosis factor super family (TNFSF) (6/8); cell growth, proliferation and differentiation (5/7); interleukins (5/9); toll‐like receptors (2/5); apoptosis (3/7) and antigen presentation (1/7), where the ratio denotes higher expressed genes to total number of genes. Statin therapy reversed expression of thirteen of these mRNAs in FH children. Conclusion FH children display higher PBMC expression of immune‐related genes mapped to several pathways, including T and B cells, and TNFSF than healthy children. Our results suggest that LDL‐C plays an important role in modulating expression of different immune‐related genes, and novel data on the involvement of these pathways in the early atherosclerosis may represent future therapeutic targets for prevention of atherosclerotic progression.

Children with familial hypercholesterolemia display changes in LDL and HDL function: A cross‐sectional study

“…Aggregation of LDL particles typically occurs following their retention in the arterial subendothelial intimal layer [1,2,[30][31][32], but our present results suggest that lipoproteins in FH subjects are primed for aggregation already while circulating in the blood, potentially due to their increased residence time in plasma caused by the underlying LDLR defect. In line with this, we previously showed that FH children have higher circulating levels of oxidized LDL [33] and display a shift in blood monocytes toward a more pro-inflammatory phenotype We also observed previously that peripheral blood mononuclear cells in FH children are characterized by a pro-inflammatory phenotype, which can be partially normalized upon initiation of statin treatment [34]. Along with the isolated hypercholesterolemia, these alterations in FH subjects could help explain their elevated risk of ASCVD [35][36][37].…”

“…In line with this, we previously showed that FH children have higher circulating levels of oxidized LDL [33] and display a shift in blood monocytes toward a more pro-inflammatory phenotype [18]. We also observed previously that peripheral blood mononuclear cells in FH children are characterized by a pro-inflammatory phenotype, which can be partially normalized upon initiation of statin treatment [34]. Along with the isolated hypercholesterolemia, these alterations in FH subjects could help explain their elevated risk of ASCVD [35][36][37].…”

Children with familial hypercholesterolemia display changes in LDL and HDL function: A Cross-sectional study

“…In line with this, we previously showed that FH children have higher circulating levels of oxidized LDL (29) and display a shift in blood monocytes towards a more proinflammatory phenotype (12). We also observed previously that peripheral blood mononuclear cells (PBMCs) in FH children are characterized by a pro-inflammatory phenotype, which can be partially normalized upon initiation of statin treatment (30). Along with the isolated hypercholesterolemia, these alterations in FH subjects could help explain their elevated risk of ASCVD (31)(32)(33).…”

Children with familial hypercholesterolemia display changes in LDL and HDL function: a cross-sectional study

“…In line with this, we previously showed that FH children have higher circulating levels of oxidized LDL (29) and display a shift in blood monocytes towards a more proinflammatory phenotype (12). We also observed previously that peripheral blood mononuclear cells (PBMCs) in FH children are characterized by a pro-inflammatory phenotype, which can be partially normalized upon initiation of statin treatment (30). Along with the isolated hypercholesterolemia, these alterations in FH subjects could help explain their elevated risk of ASCVD (31)(32)(33).…”