Approved Research

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

IRCCS Multimedica Research Hospital

Lay summary

Short leukocyte telomere length (LTL), a marker of cellular aging, predicts increased occurrence of atherosclerotic cardiovascular disease (ACVD) over time. Premature ACVD during early decades of life characterizes the clinical phenotype of carriers (even in heterozygosis) of loss of function (LoF) mutations on the gene coding for the low-density lipoprotein receptor (LDLR) which results in Familial Hypercholesterolemia (FH).

Our project aims to assess:

1) The relationship between the clinical suspicion or the definite clinical diagnosis of FH and premature LTL shortening. To address this scientific question, we aim to correlate LTL with the pathognomonic features of a suspected or definite FH diagnosis, according to validated criteria currently used in clinical practice.

2) Whether shorter LTL in suspected or definite FH predicts higher risk of ACVD occurrence over time. To investigate this point, we will take advantage of the information about occurring ACVD over subsequent follow-up visits of the 472,174 UK Biobank participants for whom LTL measurement at baseline is available.

Plasma "omics" can be exploited to identify biomarkers of prevalent or incident cardiovascular events. Specific biomarkers outperform the classical risk factors in predicting increased risk of events also in individuals who, although being younger, are at higher risk due to other factors that are not currently captured by the clinical algorithms; consequently, these subjects may be inaccurately classified as 'low risk' individuals.

This is the case of FH individuals (at least heterozygous probands), who do not always display very high LDL-cholesterol levels or present with levels comparable to those of hypercholesterolemic subjects even without FH-associated mutations ("non-FH").

On this premise, the new scope will include the following tasks:

1) Finding plasma biomarkers, or specific clusters of them, that uniquely identify FH from the "non-FH" and the rest of the population displaying low or "normal" cholesterol levels;

2) Testing whether these markers also associate with increased atherosclerotic burden of FH and predict higher occurrence of clinically overt cardiovascular diseases in FH but not in non-FH.

To pursue these tasks, we will interrogate the Olink Explore proteomics and the Nightingale metabolomic platforms currently available for individuals enrolled in the UK-Biobank who can be identified as FH subject on genetic and biological grants.