Causal associations between telomere length and pulmonary arterial hypertension: A two-sample Mendelian randomization study

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by elevated pulmonary artery pressure, leading to right heart failure, and mortality. The role of telomere length, a marker of biological aging, in PAH remains unclear. We utilized summary-level data from genome-wide association studies for various measures of telomere length and PAH. Single nucleotide polymorphisms associated with telomere length at a genome-wide significance level were used as instrumental variables. The inverse variance weighted method was the primary analysis, with sensitivity analyses including the weighted median and Mendelian randomization-Egger regression. The odds ratios and 95% confidence intervals (CI) were calculated to estimate the causal effect of telomere length on PAH risk. The Mendelian randomization analyses revealed no significant causal association between overall telomere length and PAH (odds ratios per standard deviation increase = 1.229, 95% CI: 0.469-3.222, P = .676). Similar null findings were observed for granulocyte, lymphocyte, naive T-cell, memory T-cell, B-cell, and natural killer-cell telomere lengths. Sensitivity analyses confirmed the robustness of the results, with no evidence of horizontal pleiotropy or significant influence of individual single nucleotide polymorphisms on the overall estimates. This Mendelian randomization study didn't support a causal association between telomere length and PAH.

Figure 1.

The design of the present Mendelian randomization study. This figure illustrates a Mendelian randomization framework used to investigate the causal relationship between telomere length and pulmonary arterial hypertension. Arrows depict the hypothesized causal pathways, with genetic instruments estimating the effect of telomere length on pulmonary arterial hypertension. Crosses on confounder pathways indicate the exclusion of these variables from the causal pathway in the Mendelian randomization analysis, enhancing the validity of the causal inferences. IVs = instrumental variables; NK = natural killer; SNPs = single nucleotide polymorphisms.

Figure 2.

The scatter plot for the causations between telomere length and the risk of PAH. MR: Mendelian randomization; PAH: pulmonary arterial hypertension; SNP, single nucleotide polymorphism.

Figure 3.

The scatter plot for the causations of other telomere lengths on PAH. Notes: The causations of granulocyte telomere length (A), memory T-cell telomere length (B), naive T-cell telomere length (C), lymphocyte telomere length (D), B-cell telomere length (E), NK-cell telomere length (F) on the risk of PAH. MR = Mendelian randomization; NK = natural killer; PAH = pulmonary arterial hypertension; SNP = single nucleotide polymorphism.

Figure 4.

The forest plot for the causations between telomere length and the risk of PAH. CI: confidence intervals; OR: odds ratios; PAH: pulmonary arterial hypertension.

Figure 5.

The Mendelian Randomization effect size for the causations between telomere length and PAH. Notes: The MR effect size for the causations between granulocyte telomere length (A), memory T-cell telomere length (B), naive T-cell telomere length (C), lymphocyte telomere length (D), B-cell telomere length (E), NK-cell telomere length (F) and the risk of PAH. MR = Mendelian randomization; NK = natural killer; PAH = pulmonary arterial hypertension.

Figure 6.

The leave-one-out analysis for the causations between telomere length and PAH. Notes: The leave-one-out analysis for the causations between granulocyte telomere length (A), memory T-cell telomere length (B), naive T-cell telomere length (C), lymphocyte telomere length (D), B-cell telomere length (E), NK-cell telomere length (F) and the risk of PAH. MR = Mendelian randomization; NK = natural killer; PAH = pulmonary arterial hypertension.