Clinica chimica acta; international journal of clinical chemistry · 2025
Integrative analysis of miRNAs and proteins in plasma extracellular vesicles of patients with familial hypercholesterolemia.
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Freitas Renata Caroline Costa de, Bortolin Raul Hernandes, Kuraoka Shiori, Rogers Maximillian A, Blaser Mark C, Chelvanambi Sarvesh, Borges Jessica Bassani, Oliveira Victor Fernandes de, Dagli-Hernandez Carolina, Bastos Gisele Medeiros, Marçal Elisangela da Silva Rodrigues, Malaquias Vanessa Barbosa, Gonçalves Rodrigo Marques, Faludi Andre Arpad, Silbiger Vivian Nogueira, Luchessi André Ducati, Aikawa Masanori, Hirata Rosario Dominguez Crespo, Singh Sasha A, Aikawa Elena, Hirata Mario Hiroyuki
Аннотация
BACKGROUND AND AIMS: Familial Hypercholesterolemia (FH) is a monogenic disease that leads to early-onset atherosclerosis. Causative mutations in FH-related genes are found in 60-80 % of patients, while epigenetic factors may contribute to mutation-negative cases. This study analyzed miRNAs and proteins from plasma-derived extracellular vesicles (EVs) of FH patients to explore their contribution in FH diagnosis.
METHODS: Clinical and laboratory data were obtained from 54 FH patients and 38 normolipidemic individuals. FH-related gene variants were identified using exon-targeted gene sequencing. Plasma EVs miRNome and proteome were analysed using small RNA sequencing and liquid chromatography/mass spectrometry.
RESULTS: Thirteen FH patients carried LDLR deleterious variants (MD group), while 41 did not (non-MD group). Over 2000 miRNAs were detected in plasma EVs, with miR-122-5p higher in FH patients compared to controls, and miR-21-5p higher in the MD group than in the non-MD group (p < 0.05). Proteomic analysis identified 300 proteins with 18 out of 38 proteins more abundant in EVs than in total plasma. Eighteen EVs-derived proteins had differential abundance in FH patients compared to control group (p < 0.05). EV levels of miR-122-5p, miR-21-5p and 12 proteins were correlated with serum lipids (p < 0.05). The integrative analysis between dysregulated miRNAs (miR-122-5p and miR-21-5p) and altered proteins (APOD, APOF, MBL2 and MASP1) from EVs identified several common pathways involved in cholesterol metabolism.
CONCLUSION: Co-regulation of plasma EVs miR-122-5p, miR-21-5p, APOD, APOF, MBL2 and MASP1 and their correlation with serum lipids suggest their involvement in impaired cholesterol metabolism and may be useful as biomarkers of FH severity.
METHODS: Clinical and laboratory data were obtained from 54 FH patients and 38 normolipidemic individuals. FH-related gene variants were identified using exon-targeted gene sequencing. Plasma EVs miRNome and proteome were analysed using small RNA sequencing and liquid chromatography/mass spectrometry.
RESULTS: Thirteen FH patients carried LDLR deleterious variants (MD group), while 41 did not (non-MD group). Over 2000 miRNAs were detected in plasma EVs, with miR-122-5p higher in FH patients compared to controls, and miR-21-5p higher in the MD group than in the non-MD group (p < 0.05). Proteomic analysis identified 300 proteins with 18 out of 38 proteins more abundant in EVs than in total plasma. Eighteen EVs-derived proteins had differential abundance in FH patients compared to control group (p < 0.05). EV levels of miR-122-5p, miR-21-5p and 12 proteins were correlated with serum lipids (p < 0.05). The integrative analysis between dysregulated miRNAs (miR-122-5p and miR-21-5p) and altered proteins (APOD, APOF, MBL2 and MASP1) from EVs identified several common pathways involved in cholesterol metabolism.
CONCLUSION: Co-regulation of plasma EVs miR-122-5p, miR-21-5p, APOD, APOF, MBL2 and MASP1 and their correlation with serum lipids suggest their involvement in impaired cholesterol metabolism and may be useful as biomarkers of FH severity.