No Genetic Causal Association between Periodontitis and Autoimmune Thyroiditis: A Bidirectional Two-Sample Mendelian Randomization Analysis

doi:10.21203/rs.3.rs-4247360/v1

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No Genetic Causal Association between Periodontitis and Autoimmune Thyroiditis: A Bidirectional Two-Sample Mendelian Randomization Analysis

https://doi.org/10.21203/rs.3.rs-4247360/v1

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Background Recent studies have reported associations between periodontitis and autoimmune disorders; however, it remains unclear whether the association between periodontitis and autoimmune thyroiditis (AIT) is causal. The purpose of this study was to investigate the causal association between periodontitis and AIT.

Methods We conducted a two-sample bidirectional Mendelian randomization (MR) analysis using publicly available genome-wide association study (GWAS) statistics. The single-nucleotide polymorphisms (SNPs) for AIT were derived from 244 patients and 187,684 controls. The pooled periodontitis association data included up to 17,353 individuals. The inverse-variance weighted (IVW)

method was used for the primary analysis. We applied two complementary

methods, the weighted median and MR-Egger. Then, these causal estimates were expressed as dominance ratios [odds ratios (ORs)].

Results Genetically determined AIT did not have a causal effect on probing depth (PD) (IVW OR = 0.998, 95% confidence interval (CI) = 0.948 ~ 1.051, p = 0.952). Furthermore, we did not find a significant causal effect of PD on AIT in the reverse MR analysis (IVW OR = 1.044, 95% confidence interval (CI) = 0.789 ~ 1.382, p = 0.759). The MR-Egger regression and weighted median

results were consistent with those of the IVW

method. Horizontal pleiotropy was unlikely to distort the causal estimates according to the sensitivity analysis.

Conclusion Within the limits of MR studies, the outcomes neither supported periodontitis affecting autoimmune thyroiditis nor autoimmune thyroiditis affecting periodontitis.

Periodontitis

Autoimmune thyroiditis

Causality

Mendelian randomization

Autoimmune thyroiditis (AIT), predominantly represented by Hashimoto's disease, is the prevailing autoimmune disorder affecting the thyroid gland within the populace. It is estimated to impact approximately 5% of the general population[1–3]. Autoimmune thyroiditis (AIT) primarily manifests as hypothyroidism, with the predominant causative factor being autoimmunity[4]. Oral manifestations include macroglossia, dysgeusia, delayed root resorption, reduced salivary gland secretion, compromised periodontal health, delayed wound healing, and temporomandibular joint (TMJ) osteoarthritis[5].

Periodontitis is an inflammatory condition affecting the oral cavity, that is precipitated by bacterial invasion of the periodontal tissues, and has garnered substantial epidemiological attention in the context of autoimmune disorders[6–8]. This microbial infiltration triggers a cascade of events culminating in the gradual resorption of alveolar bone and subsequent tooth loss[9–11]. Periodontitis impacts approximately 50% of adults, with approximately 10% experiencing severe forms of the condition[12]. Periodontal disease is characterized by progressive deterioration of the supportive tissues encircling the teeth, concomitant with a combined humoral and cellular immune reaction to bacterial antigens within dental plaque that gathers at the dento-gingival junction[13, 14].

The impact of thyroid hormones on periodontal health has been investigated through animal studies. Hypothyroidism amplifies bone loss associated with periodontitis by increasing the number of cells involved in bone resorption[15]. One study highlighted the impact of thyroid dysfunction, encompassing both hypothyroidism and hyperthyroidism, on oral health status. Compared with children in the control group, children affected by thyroid disorders exhibited a greater prevalence of dental caries and periodontal disease[16]. In addition, a preliminary study suggested that individuals experiencing comorbidity of type 1 diabetes and thyroiditis exhibit improved gingival health compared to those with only type 1 diabetes and no thyroid disease[17].Biological plausibility supports a potential association between Hashimoto's thyroiditis and periodontal disease. However, insufficient studies currently exist to definitively establish a causal link between these two pathologies[18].

Mendelian randomization (MR) constitutes a statistical method employing genetic variants as instrumental variables (IVs) to assess the causal association between an exposure factor and an outcome. Compared to observational studies, this method yields robust evidence of causality by mitigating confounding factors and the bias of reverse causation[19]. We conducted a bidirectional Mendelian randomization (MR) investigation into the relationship between periodontitis and autoimmune thyroiditis, complemented by a series of sensitivity analyses to address pleiotropic single nucleotide polymorphisms (SNPs) linked to potential confounding variables.

Study design and data sources

To obtain reliable results, IVs must satisfy three key assumptions in the MR analysis process[20]:(1) there is a strong relationship between the instruments and exposure(“association”); (2) genetic variables are unrelated to confounding variables of exposure outcomes (“exchangeability”); (3) the tool influences outcomes through exposure(“exclusion limit”); The bidirectional MR design flow between periodontitis and AIT is shown in Fig. 1.

The GWAS summary data used for our study are publicly available. The publicly available summary statistical datasets sets of a GWAS for AIT included 187,928 individuals (cases = 244, controls = 187,684) of European ancestry with the GWAS ID number fnn-b-E4_THYROIDITAUTOIM (https://storage.googleapis.com/finngen-public-data-r9/summary_stats/finngen_R9_E4_THYROIDITAUTOIM.gz). The periodontitis summary statistics were obtained from the most recent meta-analysis of the GWAS of the Gene–Lifestyle Interaction in the Dental Endpoints Consortium. This study is the largest to date, encompassing 17,353 clinically diagnosed patients and 28,210 controls. Cases of periodontitis are defined by either the Centers for Disease Control and Prevention/American Academy of Periodontology definitions (CDC/AAP)[21] or the Community Periodontal Index (CPI). GWAS analyses were performed specifically on individuals of European ancestry. Detailed population characteristics and specific trait definitions are further expounded upon in the source articles accompanying these summary genetic association estimates. All GWAS data utilized in this study adhered to the guidelines set forth in the Declaration of Helsinki from 1975 (amended in 2013).

Selection of the Genetic Instruments

To filter eligible genetic IVs that fulfilled the three core MR assumptions, we performed a set of quality control techniques. To address the initial hypothesis, we constructed candidate IVs utilizing summary statistics derived from exposure-associated SNPs displaying genome-wide significance (p < 5e^− 6). By employing the clumping technique with R² < 0.001 and a 10,000 kb window size for each exposure, we filtered out SNPs demonstrating significant linkage disequilibrium, ensuring independence among instrumental factors. Additionally, SNPs with minor allele frequencies < 0.01 were excluded. Furthermore, we computed the F statistics for each SNP individually using the formula F = R² × (N − 2) / (1 - R²), where R² represents the variance of exposure explained by each IV. SNPs with F > 10 were included. In accordance with the second hypothesis of Mendelian randomization (MR), the PhenoScanner database (http://www.Phenoscanner.cam.ac.uk/) was used to discern SNPs potentially linked to confounding factors, which were subsequently eliminated from the analysis. Following meticulous screening procedures, the SNPs that remained were deemed suitable instrumental variables (IVs) for our analysis.

MR analyses

To explore potential causal relationships between autoimmune thyroiditis (AIT) and periodontitis, we employed three MR techniques: inverse variance weighting (IVW)[22], MR-Egger regression[23], and weighted median (WM) regression[23]. The inverse variance weighted (IVW) method serves as the primary statistical approach due to its ability to yield the most precise estimate[24]. In evaluating causality, both MR-Egger regression and the weighted median (WM) method are comparable alternatives to the IVW method. The MR-Egger regression slope delineates the potential causal impact in addition to its intercept term, aiding in the evaluation of horizontal multiplicity[25]. Moreover, the WM method ensures a consistent analysis of multiple genetic instruments by deriving a single WM estimate; even if as many as 50% of SNPs serve as invalid genetic instruments, the results offer dependable causal estimations[23].

Pleiotropy and sensitivity analysis

We utilized the IVW and MR-Egger methods to assess heterogeneity for each individual SNP. The degree of heterogeneity among SNPs was evaluated by employing the heterogeneity statistic Q and examining the funnel plot[26]. Additionally, a leave-one-out sensitivity analysis was conducted to ascertain whether the outcomes of the Mendelian randomization investigation were impacted by any individual SNP[26].

The "Two SampleMR" [27]packages were employed consistently across all studies. A presumed causal relationship was considered statistically supported if the observed P value was < 0.05.

Instrumental Variables

In evaluating the instrumental variables based on precise screening criteria, 5 SNPs were discerned when AIT was used as the exposure instrumental variable. Conversely, the use of periodontitis as an exposure variable resulted in the identification of 8 distinct SNPs as instrumental variables.

Analysis of the bidirectional causal effect between AIT and periodontitis

Instrumental variable weighted (IVW) analysis indicated that AIT had no discernible causal effect on periodontitis (OR = 0.998, 95% CI = 0.948 ~ 1.051, P = 0.952). Conversely, the investigation revealed no significant causal impact of periodontitis on AIT (OR = 1.045, 95% CI = 0.789 ~ 1.382, P = 0.759). The results from the bidirectional analysis using the MR-Egger and WM methods were consistent with those obtained via the IVW approach. (Table 1 Fig. 2)

Table 1

Summary statistics for the MR analysis examining the potential causal effect of periodontitis on AIT (and vice versa).
Exposure	Outcome	Methods	OR	95%CI	P.value *
AIT	Periodontitis	IVW	0.998	0.948 ~ 1.051	0.952
		MR-Egger	1.110	0.884 ~ 1.393	0.433
		WM	0.984	0.928 ~ 1.044	0.603
Periodontitis	AIT	IVW	1.044	0.789 ~ 1.382	0.759
		MR-Egger	1.082	0.775 ~ 1.511	0.656
		WM	1.025	0.731 ~ 1.437	0.882

AIT, Autoimmune thyroiditis; IVW, Inverse variance weighted; WM, Weighted median; OR, Odds ratio; CI, Confidence interval; P.value *<0.05 was considered as an indication of statistical significance.

Sensitivity Analyses

When considering AIT as the exposure and periodontitis as the outcome, the Cochran’s Q statistic indicated no evidence of heterogeneity in causal inferences (MR-Egger p = 0.954 and IVW p = 0.876). Calculation of the intercept term for the MR-Egger regression revealed no presence of horizontal pleiotropy among the seven selected SNPs (intercept = -0.042; standard error 0.045, p = 0.416). The sensitivity analysis conducted with periodontitis as the exposure and AIT as the outcome revealed no notable presence of heterogeneity or horizontal pleiotropy (Table 2). The leave-one-out analysis results suggested that the association between AIT and periodontitis risk does not rely on individual SNPs, confirming the robustness and reliability of the Mendelian randomization (MR) findings (Fig. 3).

Table 2

Heterogeneity and MR-Egger test for directional pleiotropy
Heterogeneity
		MR-Egger			IVW
Exposure	Outcome	Q	df	P.value*	Q	df	P.value *
AIT	Periodontitis	0.327	3	0.954	1.210	4	0.876
Periodontitis	AIT	1.431	6	0.963	1.582	7	0.979
MR-Egger test for directional pleiotropy
Exposure	Outcome	Intercept		Se	P.value*
AIT	Periodontitis	-0.042		0.045	0.416
Periodontitis	AIT	-0.016		0.041	0.711

Q, Heterogeneity statistic Q; df, degree of freedom; se, standard error; P.value*<0.05 was considered as an indication of statistical significance.

To our knowledge, this study marks the initial application of a two-sample MR method to investigate the potential causal relationship between AIT and periodontitis within European ancestry populations, assessing causality bidirectionally. Overall, our findings do not substantiate the presence of a reciprocal genetic predisposition linking these two conditions.

Human clinical studies have indicated a deteriorated periodontal status among patients with thyroid disease[5, 17]. There are several possible explanations for the association between periodontitis and AIT. First, the impact of thyroid hormone on periodontal health has been scrutinized in animal research. Hypothyroidism amplifies periodontitis-associated bone loss by increasing the quantity of resorbed cells[15]. Second, thyroiditis initiates low-grade inflammation through diminished nitric oxide availability and heightened levels of serum prostaglandins, cytokines, and matrix metalloproteinases (MMPs). This cascade ultimately contributes to compromised periodontal health and the resorption of alveolar bone[28]. Third, vascular alterations within the interdental papilla are evident in Hashimoto's thyroiditis (HT) patients. Patients with HT exhibit a discernible decrease in capillary caliber alongside an increased count and convoluted nature of capillary loops. Microvascular changes within the interdental papilla may constitute a potential risk factor for the intricate orchestration of local periodontal defense mechanisms, suggesting a consequential association with periodontal disease[29]. Disrupted gingival microcirculation can compromise the primary line of defense, increasing the levels of prostaglandin E, cytokines, and oxidative stress, thereby contributing to the onset of periodontitis[30]. Moreover, research suggests that 79% of the likelihood of developing AIT is linked to genetic factors, with environmental factors contributing to the remaining 21%. Notably, among the identified AIT susceptibility genes are immune-modulating genes such as major histocompatibility complex (MHC), cytotoxic T lymphocyte antigen-4 (CTLA-4), CD40, and protein tyrosine phosphatase-22 (PTPN22)[31]. Studies have indicated that variants in the CTLA-4 gene may be linked to susceptibility to particular forms of periodontitis and could contribute to the development of chronic periodontitis (CP)[32].

Several plausible explanations account for the disparate findings observed. First, the association between AIT and periodontitis may be incidental, representing a concurrent phenomenon. Second, the GWAS data on AIT and PD are imperfect, and further GWAS are essential to enhance the reliability of the conclusions. Third, the influence of confounding factors on clinical studies demands consideration as a potential contributor to the observed variations.

Nevertheless, the present study has several limitations. First, the primary MR approach heavily relies on the inference of SNPs identified through GWAS. However, due to the varying quality control standards applied across individual GWASs, mitigating potential confounding biases posed a considerable challenge in our study, impacting the accuracy of the results. Second, the instrumental variables employed for periodontitis exhibited weak associations, with p values resting at 5 × 10^− 6, falling short of the conventional threshold of 5 × 10^− 8. Third, our study's population restriction to individuals of European ancestry necessitates caution when extrapolating these findings to other populations, limiting the generalizability of our conclusions. Hence, there is a need for further well-constructed prospective studies aimed at reducing observational study biases. In addition, the results must be treated rationally, and replication of our MR analysis using more complete GWAS datasets is necessary. The forthcoming accessibility of augmented data capable of elucidating a greater proportion of phenotypic variance holds potential for uncovering additional evidence supporting a causal nexus between AIT and periodontitis.

In this bidirectional MR study, our investigation did not yield substantial evidence supporting a bidirectional genetic predisposition between periodontitis and AIT. Our findings suggest the absence of a significant genetic liability shared between these conditions. However, additional GWASs are necessary to delve deeper into these outcomes and ascertain their consistency.

AIT

Autoimmune thyroiditis

Mendelian randomization

GWAS

Genome-wide association study

SNP

Single nucleotide polymorphism

IVW

Inverse-variance weighted

Probing depth

IVs

Instrumental variables

Weighted median.

Acknowledgements

The authors are grateful to the investigators involved in the original GWAS for sharing the summary data used in this study.

Authors’ contributions

Bitong Zhang and Xiuyun Ren contributed to the study design; Zhongqian Mi, Rui Cheng and Jinhua Gao acquired and analyzed the data for the MR analysis; Bitong Zhang wrote the draft of the papers; Xiuyun Ren revised and refined the manuscript; Bitong Zhang, Huiyu Shang, Xinjie Qiu, Miaomiao Zhao, Xuedan Yan and Rui Cheng contributed to data interpretation; All authors approved the final draft and accepted the decision to submit the manuscript for publication; Xiuyun Ren and Rui Cheng contributed to funding acquisition.

Funding

This study was supported by the Local Science and Technology Development Fund Project guided by the Central Government of Shanxi Provincial Department of Science and Technology (Grant/Award Number: YDZX202014000011310) and the Science and Technology Innovation Project of Higher Education Institutions of Shanxi Province, (Grant/Award Number: 2022L167, 2022L145).

Data Availability

All data generated or analyzed during this study are included in this published article and its additional material.

The publicly available summary statistical datasets sets of a GWAS for AIT of European ancestry with the GWAS ID number fnn-b-E4_THYROIDITAUTOIM (https://storage.googleapis.com/finngen-public-data-r9/summary_stats/finngen_R9_E4_THYROIDITAUTOIM.gz). The periodontitis summary statistics were obtained from the most recent meta-analysis of the GWAS of the Gene–Lifestyle Interaction in the Dental Endpoints Consortium. (https://pubmed.ncbi.nlm.nih.gov/31235808/).

Competing interests

All authors have declared that no conflicts of interest exist.

Ethics approval and consent to participate

Not applicable. The data used for analysis were obtained from published studies and public databases. The GWAS database is a database of publicly available datasets, where each study has been approved by local institutional review boards and ethics committees.

Consent for publication

Not applicable.

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No competing interests reported.

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You are reading this latest preprint version

No Genetic Causal Association between Periodontitis and Autoimmune Thyroiditis: A Bidirectional Two-Sample Mendelian Randomization Analysis

Status:

Version 1

Abstract

Figures

Introduction

Materials and methods

Study design and data sources

Selection of the Genetic Instruments

MR analyses

Pleiotropy and sensitivity analysis

Results

Instrumental Variables

Analysis of the bidirectional causal effect between AIT and periodontitis

Sensitivity Analyses

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1