Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Centre for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Centre of Zhejiang University, China
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, China
- School of Stomatology, Zhejiang Chinese Medical University, China
- Department of Epidemiology, School of Public Health Zhejiang Chinese Medical University, China
Figures
Figure 1
Study design.
(A) Overview of the process and principal assumptions of MR. (B) Data sources of the GWASs. (C) Methods performed in the present study. Abbreviations and Notes: BCC, Blood Cell Consortium; BMA, …
Figure 2 with 2 supplements
Results of the UVMR.
(A) A circular heatmap representing the MR analyses for the associations between circulating immune cells and the risk of periodontitis. Lines, from outermost to innermost, represent IVW, MR-WM, …
Figure 2—figure supplement 1
Scatter plots to explore outliers for two features with considerable heterogeneity.
Based on the RadialMR method, we detected 1, 21, 1, and 14 outlier SNPs from the memory B cell (A), the monocyte (B), the natural killer T cell (C), and the neutrophil (D), respectively. …
Figure 2—figure supplement 2
Results of leave-one-out sensitivity analysis.
No influential SNPs were detected for either the neutrophil (A), the natural killer T cell (B), or the plasmacytoid DC (C). Abbreviations: DC, dendritic cell; MR, Mendelian randomization; SNP, …
Figure 3 with 1 supplement
Results of the subgroup and reverse MR.
(A) A circular heatmap illustrates the results of the subgroup analysis and reverse MR. Lines in the heatmap represent periodontitis (GLIDE), chronic periodontitis (FinnGen), chronic gingivitis …
Figure 3—figure supplement 1
Scatter plots of the estimated effects in the subgroup MR.
The effect estimates for each variant in B cell (CP) (A), plasmacytoid DC (CP) (B), B cell (GH) (C), and CD4+ T cell (CG) (D) are provided by plotting SNP–outcome associations against SNP–exposure …
Figure 4
Results of the MVMR.
(A) A heatmap represents the results of the MVMR. Rows and columns correspond to exposures and adjustment factors, respectively. The color scale of the heatmap is determined by the odds ratio (OR). …
Figure 5 with 1 supplement
Results of the TWAS and colocalization analysis.
(A) A Venn diagram illustrates the intersecting genes shared by multiple traits (p < 0.05). (B) A heatmap representing the TWAS and colocalization analysis for five genes interacting among …
Figure 5—figure supplement 1
Manhattan plots for natural killer T and plasmacytoid DC.
The Manhattan plot illustrates gene–trait associations for plasmacytoid DC (A) and natural killer T (B). The x-axis represents the genomic position. The blue lines indicate a Z-score of 1.96. The …
Tables
Table 1
Characteristics of the GWAS data for MR.
| Phenotype | Year | Sample size (n case/n control) | n SNP (million) | Ancestry | Unit | Consortium/cohort | PMID |
|---|---|---|---|---|---|---|---|
| Exposure | |||||||
| Circulating immune cells | 2020 | 563,946 | 15 | European | nl | BCC | 32888494 |
| Lymphocyte subsets | 2020 | 3757 | 15.2 | European | µg | Sardinian cohort | 32929287 |
| Outcome | |||||||
| Periodontitis | 2019 | 35,096 (12,251/22,845) | 10.8 | European | Event | GLIDE | 31235808 |
| Chronic periodontitis (FinnGen) | 2023 | 263,668 (4434/259,234) | 20.2 | European | Event | FinnGen (R9K11) | 36653562 |
| Chronic gingivitis (FinnGen) | 2021 | 196,245 (850/195,395) | 16.4 | European | Event | FinnGen (R5K11) | |
| Gingival hyperplasia (FinnGen) | 2023 | 259,613 (379/259,234) | 20.2 | European | Event | FinnGen (R9K11) | |
| Covariate | |||||||
| Cigarettes smoked per day | 2019 | 249,752 | 12 | European | 1/SD | GSCAN | 30643251 |
| Fasting plasma glucose | 2021 | 200,622 | 31 | European | mmol/l | MAGIC | 34059833 |
| Body mass index | 2018 | 681,275 | 2.3 | European | kg/m2 | GIANT | 30124842 |
Table 2
Ranking of risk factors and models for periodontitis in MR-BMA analysis.
| Trait | Ranking by MIP | MIP | MACE | Ranking by PP | PP | MSCE |
|---|---|---|---|---|---|---|
| Neutrophil | 1 | 0.895 | 0.097 | 1 | 0.771 | 0.108 |
| Natural killer T cell | 2 | 0.135 | −0.003 | 2 | 0.056 | −0.017 |
| Plasmacytoid DC | 3 | 0.102 | 0 | 3 | 0.045 | 0.007 |
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DC, dendritic cell; MACE, average causal effect of risk factor model; MIP, marginal inclusion probability; MR-BMA, Mendelian randomization-Bayesian model averaging; MSCE, model-specific causal estimates; PP, poster probability.
Table 3
TWAS and colocalization analysis identified genes involved in multiple phenotypes.
| Gene name | Position | Phenotype | TWAS Z-score | TWAS p val | Perm p val | Model p val | PP.H3 | PP.H4 |
|---|---|---|---|---|---|---|---|---|
| S100A9 | 1q21.3 | Neutrophil | 7.225 | 5.0 × 10−13 | 0 | 1.7 × 10−17 | 0.035 | 0.962 |
| Periodontitis | −3.564 | 3.7 × 10−4 | 1.3 × 10−3 | 1.7 × 10−17 | 0.008 | 0.259 | ||
| S100A12 | 1q21.3 | Neutrophil | 7.310 | 2.7 × 10−13 | 1.7 × 10−4 | 4.1 × 10−43 | 0.027 | 0.970 |
| Periodontitis | −3.513 | 4.4 × 10−4 | 8.1 × 10−4 | 4.1 × 10−43 | 0.008 | 0.244 | ||
| MCM6 | 2q21.3 | Neutrophil | −5.549 | 2.9 × 10−8 | 0 | 3.5 × 10−13 | 0 | 0.999 |
| Plasmacytoid DC | 7.172 | 7.4 × 10−13 | 2.7 × 10−3 | 3.5 × 10−13 | 1.000 | 0 | ||
| PI4KAP2 | 22q11.21 | Neutrophil | 5.345 | 9.0 × 10−8 | 3.3 × 10−3 | 3.7 × 10−39 | 0.003 | 0.016 |
| Plasmacytoid DC | 5.322 | 1.0 × 10−7 | 3.2 × 10−3 | 3.7 × 10−39 | 0.009 | 0.045 |
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DC, dendritic cell; Perm, permutation test; PP, posterior probability; TWAS, transcriptome-wide association study.
Author response table 1
Organizations and Samplesize in the GTEx database.
| ID | Tissue | N | ID | Tissue | N |
|---|---|---|---|---|---|
| 1 | Muscle_Skeletal | 706 | 28 | Artery_Coronary | 213 |
| 2 | Whole_Blood | 670 | 29 | Brain_Cerebellum | 209 |
| 3 | Skin_Sun_Exposed_Lower_leg | 605 | 30 | Liver | 208 |
| 4 | Artery_Tibial | 584 | 31 | Brain_Cortex | 205 |
| 5 | Adipose_Subcutaneous | 581 | 32 | Brain_Nucleus_accumbens_basal_ganglia | 202 |
| 6 | Thyroid | 574 | 33 | Brain_Caudate_basal_ganglia | 194 |
| 7 | Nerve_Tibial | 532 | 34 | Brain_Cerebellar_Hemisphere | 175 |
| 8 | Skin_Not_Sun_Exposed_Suprapubic | 517 | 35 | Brain_Frontal_Cortex_BA9 | 175 |
| 9 | Lung | 515 | 36 | Small_Intestine_Terminal_Ileum | 174 |
| 10 | Esophagus_Mucosa | 497 | 37 | Brain_Hypothalamus | 170 |
| 11 | Cells_Cultured_fibroblasts | 483 | 38 | Brain_Putamen_basal_ganglia | 170 |
| 12 | Adipose_Visceral_Omentum | 469 | 39 | Ovary | 167 |
| 13 | Esophagus_Muscularis | 465 | 40 | Brain_Hippocampus | 165 |
| 14 | Breast_Mammary_Tissue | 396 | 41 | Brain_Anterior_cingulate_cortex_BA24 | 147 |
| 15 | Artery_Aorta | 387 | 42 | Cells_EBV-transformed_lymphocytes | 147 |
| 16 | Heart_Left_Ventricle | 386 | 43 | Minor_Salivary_Gland | 144 |
| 17 | Heart_Atrial_Appendage | 372 | 44 | Vagina | 141 |
| 18 | Colon_Transverse | 368 | 45 | Brain_Amygdala | 129 |
| 19 | Esophagus_Gastroesophageal_Junction | 330 | 46 | Uterus | 129 |
| 20 | Stomach | 324 | 47 | Brain_Spinal_cord_cervical_c-1 | 126 |
| 21 | Testis | 322 | 48 | Brain_Substantia_nigra | 114 |
| 22 | Colon_Sigmoid | 318 | 49 | Kidney_Cortex | 73 |
| 23 | Pancreas | 305 | 50 | Bladder | 21 |
| 24 | Pituitary | 237 | 51 | Cervix_Endocervix | 10 |
| 25 | Adrenal_Gland | 233 | 52 | Cervix_Ectocervix | 9 |
| 26 | Spleen | 227 | 53 | Fallopian_Tube | 8 |
| 27 | Prostate | 221 | 54 | Kidney_Medulla | 4 |
Additional files
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Supplementary file 1
Case definition and exclusion criteria in included genome-wide association studies (GWASs).
Characteristics of the single-nucleotide polymorphisms (SNPs) used as instrumental variables (IVs) in the Mendelian randomization (MR). Effect estimates of causal associations between circulating immune cells and periodontitis risk. The heterogeneity and horizontal pleiotropy of the main results using Cochran’s Q-statistics and MR-Egger intercept. Effect estimates of causal associations after excluding outliers in RadialMR for two features with considerable heterogeneity. Effect estimates of causal associations after excluding influential or outlier SNPs for significant results. Effect estimates of causal associations between circulating immune cells and chronic periodontitis, chronic gingivitis, and gingival hyperplasia in subgroup analysis. Effect estimates of the reverse associations between periodontitis and circulating immune cells. Effect estimates of causal associations after mutual and covariate correction in multivariable Mendelian randomization (MVMR). Ranking of models according to their posterior probability (PP) using Mendelian randomization-Bayesian model averaging (MR-BMA) analysis. Results of transcriptome-wide association study (TWAS), conditional analysis, permutation testing, and colocalization analysis on neutrophil, natural killer T cell, plasmacytoid dendritic cell (DC), and periodontitis.
- https://cdn.elifesciences.org/articles/92895/elife-92895-supp1-v1.xlsx
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Supplementary file 2
Strengthening the Reporting of Observational Studies in Epidemiology using the Mendelian Randomization (STROBE-MR) checklist.
- https://cdn.elifesciences.org/articles/92895/elife-92895-supp2-v1.doc
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MDAR checklist
- https://cdn.elifesciences.org/articles/92895/elife-92895-mdarchecklist1-v1.pdf
