Common genetic variants in telomere genetics in colorectal cancer: a Mendelian randomisation study

BACKGROUND Telomere biology is pivotal in the development of malignant tumors, notably colorectal cancer (CRC), which is a gastrointestinal malignancies. Yet, the causal link between CRC and telomere length (TL) remains elusive AIM This study employs bidirectional Mendelian randomization analysis to probe the causal relationship between CRC and genetically determined TL. METHODS Instrumental variables were selected from single nucleotide polymorphisms (SNPs) linked to leukocyte telomere length (LTL) and colorectal cancer (CRC) in European populations. Two-sample Mendelian randomization (MR) with inverse variance weighting (IVW) was employed as the primary method. Sensitivity analyses, MR-Egger regression, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were used to evaluate pleiotropy. Bioinformatics was utilized to investigate genetic variants, key genes, pathways, and protein interactions. RESULTS Genetically determined longer telomeres were linked to increased CRC risk ((common effect model (IVW): odds ratio [OR] = 1.16, 95% confidence interval [CI]: 1.07 to 1.25, random effects model (IVW): [OR] = 1.16, 95% [CI]: 1.06 to 1.27). Sensitivity analyses corroborated findings. GO enrichment indicated enrichment in telomere maintenance, DNA repair, and protein binding. KEGG analysis highlighted pathways such as Pyrimidine metabolism and RNA degradation. CONCLUSION PARP1, TREF1, TREF2, TRET, STN1 and HSPA4 are considered key genes related to the length of long telomeres, which are associated with the development of CRC. TL significant in the Etiology of CRC.