Approved Research

Unveiling the connection between genetically determined hypercholesterolemia and premature cellular aging, marked by leukocyte telomere length shortening

Lay summary

Aims

a) To assess the relationship between clinical suspicion or definite clinical diagnosis of familial hypercholesterolemia (FH) and premature leukocytes telomere length (LTL) shortening.

b)To verify whether the link between hypercholesterolemia and premature LTL is related to the occurring atherosclerotic cardiovascular disease (ACVD) over time.

Scientific rationale

Telomere length (TL) shortening physiologically occurs over decades of age in general populations, but it is considered as a marker of vascular aging when it occurs faster as compared to that expected in advanced decades. Genetically determined FH, even in heterozygosity, results into persistently elevated low-density lipoprotein cholesterol (LDL-C) burden and oftentimes unsuspected increased risk of premature coronary heart disease (CHD) since birth up to the time of a correct diagnosis and starting of a lipid lowering treatment, which are critical issues in critical practice.

Is faster TL shortening an issue of genetically determined FH and is this linked to increased CHD risk? Data from the general population are inconclusive, with some reports suggesting a correlation between elevated LDL-C levels and shorter LTL, which was not confirmed by others.

Public health impact

We aim to find that faster TL shortening is an issue of genetically determined FH but not of clinically determined/not genetically confirmed FH. This expected message is of immediate public clinical impact, since it might set telomere length as a potential biomarker in the diagnostic research of the most severe forms of FH, for which the earliest and the most aggressive LDL-C lowering treatment is advised.

Also, these findings might entice further future analyses to favor the consideration of this marker in the drop-down diagnostic process among related individuals as TL shortening is also a partial inherited genetic trait. Vice versa, from a translational point of view, these in vivo findings might further help to add knowledge and generate further questions for the understanding of the pathological effect of cholesterol in cellular aging processes.