Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors

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RESEARCH PRODUCT

Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors

A. Moregola Fabio Pellegatta Maurizio Averna Alberico L. Catapano V. Zampoleri Rossella Spina Angelo Baldassarre Cefalù Fabrizia Bonacina Lorenzo Da Dalt Liliana Grigore Andrea Baragetti Giuseppe Danilo Norata Angela Pirillo

subject

medicine.medical_specialty Settore MED/09 - Medicina Interna Cellular ageing Epidemiology Hypercholesterolemia CD34 Cellular senescence 030204 cardiovascular system & hematology Hyperlipoproteinemia Type II 03 medical and health sciences Mice 0302 clinical medicine Internal medicine Leukocytes Medicine Animals Humans Progenitor cell Haematopoiesi 030304 developmental biology Ldl cholesterol 0303 health sciences business.industry Cholesterol LDL Telomere 3. Good health Telomere Haematopoiesis Increased risk Endocrinology medicine.anatomical_structure CHD Telomeres Bone marrow Cardiology and Cardiovascular Medicine business Familial hypercholesterolaemia

description

Abstract Aims Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects. Methods and results LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27 ± 0.07 vs. 1.59 ± 0.04, P = 0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (&lt;35 y) (1.34 ± 0.08 vs. 1.64 ± 0.08, P = 0.019); moreover, LTL was shorter in statin-naïve HeFH subjects as compared to controls (1.23 ± 0.08 vs. 1.58 ± 0.04, P = 0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33 ± 0.05 vs. 1.55 ± 0.08, P = 0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls. Conclusions We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.

year	journal	country	edition	language
2020-11-17

10.1093/eurjpc/zwaa115 http://hdl.handle.net/10447/522500