Genetic Determinants of Telomere Length and Their Role in Human Disease: Molecular Mechanisms and Underrepresented Populations’ Perspectives

Telomere length (TL) is a key determinant of cellular aging and genomic stability, influenced by genetic, molecular, and environmental factors. Progressive telomere shortening has been associated with degenerative and cardiovascular diseases, whereas longer telomeres have been linked to an increased risk of cancer, highlighting a dual and context-dependent relationship between TL and disease susceptibility. Evidence from genome-wide association studies (GWAS) and Mendelian randomization analyses indicates that TL is a highly heritable and polygenic trait, regulated by variants in genes such as TERT, TERC, RTEL1, and POT1, as well as components of the shelterin and CST complexes. This study integrates genetic variants associated with telomere shortening and elongation, including their functional classification, proposed molecular mechanisms, and ACMG/AMP categorization, together with global and Latin American allele frequency data. These variants may participate in key processes such as telomerase activity, telomerase RNA stability, and telomere replication, thereby influencing susceptibility to multiple diseases. However, current evidence is largely derived from European and Asian populations. Given the highly admixed nature of Latin American populations, population-specific studies are required to identify unique genetic determinants and to improve the application of precision medicine.