Reverse causal relationship between periodontitis and shortened telomere length: Bidirectional two-sample Mendelian random analysis

Abstract

Background: Observational studies have demonstrated a link between shortened telomere lengths(TL) and chronic periodontitis. However, whether the shortened TL is the cause or the result of periodontitis is unknown.Therefore, our objective was to investigate a bidirectional causal relationship between periodontitis and TL using a two-sample Mendel randomized (MR) study.

Methods: A two-sample bidirectional MR analysis using publicly available genome-wide association study (GWAS) data was used. As the primary analysis, inverse variance weighting (IVW) was employed. To identify pleiotropy, we used leave-one-out analysis, MR-Egger, Weighted median, Simple mode, Weighted mode, and MR pleiotropy residual sum and outlier (MR-PRESSO).

Results: In reverse MR results, a genetic prediction of short TL was causally associated with a higher risk of periodontitis (IVW: odds ratio [OR]: 1.0601, 95% confidence interval [CI]: 1.0213 to 1.1002; P =0.0021) and other complementary MR methods. In the forward MR analysis, periodontitis was shown to have no significant effect on TL (IVW: p = 0.7242), with consistent results for the remaining complementary MR. No pleiotropy was detected in sensitivity analysis (all P>0.05).

Conclusion: Our MR studies showed a reverse causal relationship, with shorten TL being linked to a higher risk of periodontitis, rather than periodontitis shorten that TL. Future research is needed to investigate the relationship between cell senescence and the disease.

Keywords: Mendelian randomization; biological aging; causality; genome-wide association studies; inflammation; periodontal disease; telomere length.

Figure 1

Study Design Sketch: Periodontitis is exposed in red in the forward MR analysis, and TL is the outcome. Exposure is represented by the color blue in the reverse MR analysis, periodontitis is the outcome. Abbreviation: TL, telomere length; MR, mendelian randomization; SNP, single nucleotide polymorphism.

Figure 2

The connection between genetically instrumented periodontitis and TL, and vice versa is estimated using MR(the table at the bottom shows the OR of TL shortening to periodontitis) CI, confidence interval; IVW, inverse variance-weighted; MR, Mendelian randomization; OR, odds ratio.

Figure 3

The reverse MR: Scatter plot of the effects of SNPs on TL and periodontitis. The horizontal and vertical axes represent the effect of each genetic variation on telomere length and periodontitis. The gray line around the black solid point indicates the corresponding 95% CI for the effect. The slopes of the solid lines show the effect estimates of the five MR methods. MR, mendelian randomization; SNP, single nucleotide polymorphism; CI, confidence interval.

Figure 4

The funnel plot of the association between periodontal and TL, reverse MR analysis;It is used to determine whether the associations observed are noticeably heterogeneous.