Assessment of bidirectional relationships between circulating cytokines and periodontitis: Insights from a mendelian randomization analysis

Abstract

Background: The purpose of this Mendelian randomization (MR) study was to assess the causal relationship between circulating cytokines and periodontitis. Materials and methods: Based on the aggregated statistics of the largest publicly available genome-wide association study (GWAS), we applied a bidirectional two-sample MR. MR analyses were conducted using Inverse variance weighted (IVW), Robust Adjusted Profile Score (RAPS), Maximum likelihood (ML), Weighted median and MR-Egger, and results obtained from IVW served as the primary outcome. Cochran Q test was used to test the heterogeneity. MR-Egger intercept test and MR polymorphism residual and outlier test (MR-PRESSO) were used for polymorphism analysis. Leave-one-out sensitivity and funnel plots were used for sensitivity analysis. Results: The IVW method indicated that interleukin 9 (IL9) had a positive causal relationship with periodontitis [odds ratio (OR) = 1.199, 95% confidence interval (CI) = 1.049-1.372, p = 0.008], and interleukin 17 (IL17) had a negative causal relationship with periodontitis (OR = 0.847, 95% CI = 0.735-0.976, p = 0.022). In bidirectional MR, periodontitis was not causally related to any of the cytokines in our study. Conclusion: Our findings provided evidence in support of potential causal associations between circulating IL9/IL17 and periodontitis.

Keywords: IL17; IL9; cytokines; mendelian randomization; periodontitis.

FIGURE 1

Study design to investigate the association between circulating cytokines and risk of periodontitis basing on bidirectional Mendelian randomization assumptions. The MR study must satisfy three assumptions. Assumption 1: genetic variation used for instrumental variable is associated with exposure; Assumption 2: genetic variation is independent of confounding factors; Assumption 3: genetic variation affects the outcome only through the exposure and not through other pathways. MR, Mendelian randomization; SNP, single-nucleotide polymorphism.

FIGURE 2

Odds ratios (95% Confidence interval) from Mendelian randomization analysis showing associations between genetically predicted cytokine levels (cut-off = p < 5 × 10⁻⁶) and risks for periodontitis. The causal association between circulating cytokine levels and periodontitis was mainly calculated through two-sample MR analysis using IVW method. Estimates with 95% CI are expressed as odds ratios for periodontitis per 1-SD increase of genetically predicted circulating cytokine levels. *, Results of MR analysis after exclusion of SNPs associated with confounding factors. **, Results of MR analysis after using a proxy SNP.

FIGURE 3

Scatter plots of potential effects of SNPs on IL9 and IL17 versus periodontitis. A, Scatter plot of potential effects of SNPs on IL9 versus periodontitis. B, Scatter plot of potential effects of SNPs on IL17 versus periodontitis. Scatter plots presented per-allele association with outcome risk plotted against the per-allele association with one standard deviation of exposure (with vertical and horizontal gray lines showing the 95% CI for each SNP). Analyses were conducted using IVW, Weighted median, Wald ratio, RAPS, MR Egger, MR-PRESSO, and ML. The slope of each line corresponding to the estimated MR effect per method. SNP, single-nucleotide polymorphism; IVW, Inverse variance weighted; ML, Maximum likelihood; MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier; RAPS, Robust Adjusted Profile Score.

FIGURE 4

Beta (±1.96*Standard error) from Mendelian randomization analysis showing associations between genetically predicted periodontitis (Cut-off = p < 5 × 10⁻⁶) and risks for cytokine levels. The causal association between periodontitis and circulating cytokine levels was mainly calculated through two-sample MR analysis using IVW method. *, Results of MR analysis after exclusion of SNPs associated with confounding factors. **, Results of MR analysis after using a proxy SNP.