| Background:Malignant brain tumors are difficult to be completely resected because of their invasion of nearby normal brain tissues,which makes them easy to recur and proliferate and expand very rapidly,resulting in poor quality of life,low survival rate,poor prognosis and difficult to be cured.The etiology and pathogenesis of intracranial malignant tumors have not been fully investigated,but previous studies have identified some risk factors associated with the development of malignant brain tumors,however,the causal relationship between these risk factors and how the tumor develops has not yet been proven.Telomeres are special structures consisting of guanine-rich multiple repetitive DNA sequences and telomere binding proteins at the end of eukaryotic chromosomes,which play a crucial role in maintaining genome integrity and regulation of gene expression.Recent studies have suggested that longer telomere length may cause an increased risk of malignant brain tumor.In previous case-control studies of telomere length-risk of malignant brain tumors,investigators have often measured telomere length after the onset of disease,and malignant brain tumors may have an effect on telomere length,i.e.,creating a reverse causality bias.Mendelian Randomization is a reliable means of causal inference,which better compensates for the shortcomings of traditional research methods and has been widely used in epidemiological studies in recent years by using published Genome-Wide Association Studies(GWAS)data.According to Mendel’s second law of inheritance-the law of free association-the offspring produced by crossing parents with two pairs of opposite traits produce gametes as alleles separate and non-alleles freely assemble,i.e.,genetic variation is inherited independently and shows randomness,and thus offspring genotypes are rarely affected by environmental confounding.At the same time,the emergence of genetic variants precedes acquired environmental confounders in time,thus minimizing the effect of reverse causality bias on the results of causal association analysis between exposure and environment.Objective:To explore the causal relationship between telomere length(TL)and the risk of malignant brain tumors using 2 Sample Mendelian Randomization(2SMR)method,and to provide a theoretical basis for the prevention and treatment of malignant brain tumors.Methods:The GWAS data of telomere length in the public database(sample size 472174)and the GWAS data of malignant brain tumors in the public database(sample size 218792)were extracted using the R package "Two Sample MR"(version 0.5.6)in Rstudio(version 4.2.2).Single Nucleotide Polymorphism(SNP)loci that were significantly associated with telomere length(genome-wide significant level P<5e-8)were extracted as genetic instrumental variables according to preset thresholds in Rstudio(version 4.2.2),and eligible SNPs were found by matching in the outcome(malignant brain tumor)GWAS database for association analysis.Inverse Variance Weighted(IVW)and MR-Egger regression methods were used to perform the 2SMR analysis,and the results were evaluated based on Odds Ratio(OR)and 95% Confidence Interval(CI).The reliability and stability of the results were verified by the Leave-One-Out method for sensitivity analysis,the Cochran Q method for heterogeneity testing,and the MR-Egger regression method for multiple validity testing.Results:A total of 137 SNPs were included in the study,and the results of IVW(OR=2.56,95% CI:1.46-4.49)and MR-Egger(OR=3.29,95%CI:1.18-9.13)analyses showed that the risk of malignant brain tumors increased with increasing telomere length,and the results were statistically significant.The "leave-one-out" method showed stable results,with no instrumental variables that fundamentally affected the results,as well as a positive causality;it also eliminated the effects of heterogeneity and genetic pleiotropy on causal inference.Conclusion:2SMR analysis showed that the risk of malignant brain tumors increases with increasing telomere length. |
