Serum anti-inflammatory and inflammatory markers have no causal impact on telomere length: a Mendelian randomization study

Abstract

Introduction: The relationship between inflammatory and anti-inflammatory markers and telomere length (TL), a biological index of aging, is still poorly understood. By applying a 2-sample Mendelian randomization (MR), we investigated the causal associations between adiponectin, bilirubin, C-reactive protein (CRP), leptin, and serum uric acid (SUA) with TL.

Material and methods: MR was implemented by using summary-level data from the largest ever genome-wide association studies (GWAS) conducted on our interested exposure and TL. Inverse variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Profile Score (RAPS), and MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. Sensitivity analysis was conducted using the leave-one-out method.

Results: With regard to adiponectin, CRP, leptin, and SUA levels, we found no effect on TL for all 4 types of tests (all p > 0.108). Results of the MR-Egger (p = 0.892) and IVW (p = 0.124) showed that bilirubin had no effect on telomere maintenance, whereas the results of the WM (p = 0.030) and RAPS (p = 0.022) were negative, with higher bilirubin concentrations linked to shorter TL. There was a low likelihood of heterogeneity for all the estimations, except for bilirubin (IVW p = 0.026, MR Egger p = 0.018). MR-PRESSO highlighted no outlier. For all the estimations, we observed negligible intercepts that were indicative of low likelihood of the pleiotropy (all p > 0.161). The results of leave-one-out method demonstrated that the links are not driven because of single nucleotide polymorphisms (SNPs).

Conclusions: Our results highlight that neither the anti-inflammatory nor pro-inflammatory markers tested have any significant causal effect on TL. The casual role of bilirubin on TL still needs to be investigated.

Keywords: C-reactive protein; Mendelian randomization; adiponectin; bilirubin; leptin; serum uric acid; telomere length.

Figure 1

A – Forest plot for adiponectin showing that no single SNPs had a significant effect on telomere length. B – Scatter plot for adiponectin showing low heterogeneity (IVW p = 0.093) TL – telomere length, SNR – single nucleotide polymorphisms, IVW – inverse variance weighted method, Adipo – adiponectin, MR – Mendelian randomization.

Figure 2

A – Forest plot for bilirubin showing that 2 out of 4 SNPs were negatively associated with telomere length (i.e. rs6431558 (β = –0.122, SE = 0.0618, p = 0.0466) and rs7587051 (β = –0.913, SE = 0.267, p = 0.0006)). B – Scatter plot for bilirubin showing heterogeneity (IVW p = 0.026; MR Egger’s p = 0.018) TL – telomere length, SNR – single nucleotide polymorphisms, IVW – inverse variance weighted method, Bili – bilirubin, MR – Mendelian randomization.

Figure 3

A – Forest plot for C-reactive protein (CRP) showing that no single SNPs had a significant effect on telomere length. B – Scatter plot for C-reactive protein (CRP) showing low heterogeneity (IVW p = 0.616) TL – telomere length, SNR – single nucleotide polymorphisms, IVW – inverse variance weighted method, CRP – C-reactive protein, MR – Mendelian randomization.

Figure 4

A – Forest plot for leptin showing that no single SNPs had a significant effect on telomere length. B – Scatter plot for leptin showing low heterogeneity (IVW p = 0.480) TL – telomere length, SNR – single nucleotide polymorphisms, IVW – inverse variance weighted method, MR – Mendelian randomization.

Figure 5

A – Forest plot for serum uric acid showing that no single SNPs had a significant effect on telomere length. B – Scatter plot for serum uric acid showing low heterogeneity (IVW p = 0.829) TL – telomere length, SNR – single nucleotide polymorphisms, IVW – inverse variance weighted method, MR – Mendelian randomization.