Telomere Length, Pathways, And Disease Associations

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Telomeres are structural DNA elements of repetitive nucleotide sequences complexed with proteins at the ends of each chromosome. They preserve chromosome stability, but also determine the replicative limits of a given cell. That is telomere length decreases with each cell division due to DNA polymerase’s inability to fully replicate the telomere. Stem cells can replicate indefinitely due to enzyme telomerase, which maintains telomere length, however in most cells once telomere length has been reduced, past a critical threshold, they can no longer divide and are said to be senescent.

Telomere length is normally determined in leukocytes (called LTL) and decreases with age. LTL at birth is 44%–86% heritable. Age associated DNA damage response foci are also found in telomeres, which may reduce the replicative capacity of cells. Genome wide association studies (GWAS) have indicated a causal role for LTL in several diseases, including coronary artery disease (CAD), abdominal aortic aneurysm, several cancers, interstitial lung disease, and celiac disease.

In an attempt to further understand this disease association a study with 96 listed authors led by Veryan Codd of NIHR Leicester Biomedical Research Centre, Glenfield Hospital, UK, performed a GWA meta-analysis of 78,592 individuals from the European Network for Genetic and Genomic Epidemiology (ENGAGE) study and from the European Prospective Investigation into Cancer and Nutrition (EPIC) Cardiovascular Disease (CVD) and InterAct studies. UK biobank was used to perform mendelian randomization (MR) association with disease. The results were published in The American Journal of Human Genetics.

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Associations of shorter LTL with increasing age and male gender were observed as expected from direct LTL testing using a normalized quantitative polymerase chain reaction method. There were 20 sentinel variants at 17 genomic loci independently associated with LTL at a level of genome-wide statistical significance (p < 5 x 108), including six loci that had not previously been associated with LTL.

Consistent with the importance of age-associated DNA damage response foci, PARP1 (a DNA damage repair enzyme) was confirmed by the new study to regulate telomere length. Reduced PARP1 activity was associated with shorter telomere length. Telomere shortening could be a mechanism of action for PARP inhibitors in cancer therapy. Other DNA damage repair proteins were also identified.

The study suggested that nucleotide metabolism is a key pathway in regulating LTL. Disrupted nucleotide homeostasis results in increased replication error, cell cycle arrest, and DNA-damage-induced apoptosis and perhaps also shorter telomeres.

The UK biobank MR analysis revealed increased risk of hypothyroidism, decreased risk of thyroid cancer, lymphoma, uterine fibroids, uterine polyps, and benign prostatic hyperplasia. Decreased risk of lung, skin cancer and leukemia in people with shorter telomeres was confirmed.

Shorter LTL also associated with rheumatoid arthritis, aortic valve stenosis, chronic obstructive pulmonary disease (COPD), CAD and heart failure as previously determined.

A current lack of large-scale data on LTL in non-European cohorts is limiting.

“In summary, our findings substantially expand current knowledge on the genetic determinants of LTL, and they elucidate genes and pathways that regulate telomere homeostasis and their potential impact on human diseases and cancer development,” stated the authors.