Introduction
Periodontitis (PD) is a common dysbiotic inflammatory disorder indicated by impaired integrity of periodontium, including alveolar bone, cementum, gingiva, and periodontal ligament [
1‐
3]. The continuous breakdown of periodontium tissue eventually leads to tooth looseness and the loss of teeth if not properly treated, which severely affects patients’ quality of life and causes enormous socioeconomic burden [
4,
5]. About 20–50% of the global population suffer from PD, while severe PD affects approximately 15% of the general population, making it a leading prevalent chronic inflammatory disease worldwide [
6,
7]. Notably, though PD has a complex etiology at multiple levels, such as dysbiotic microbes followed by destructive inflammation, previous studies have shown that genetic susceptibility greatly contributes to the etiopathogenesis of PD [
1,
8].
Sjogren’s syndrome (SS) is an autoimmune disease with unspecified etiology which primarily involves the lacrimal and salivary glands, leading to excessive xerophthalmia (dry eyes) and xerostomia (dry mouth) [
9]. Moreover, SS patients can develop many systemic manifestations due to autoimmune-mediated involvement in multiple organs, such as immune thrombocytopenia, interstitial lung disease, and cardiovascular disease [
10,
11]. Systemic sicca symptoms that can only be relieved by symptomatic treatments and possibly associated fatigue, depression, and decreased physical performance severely jeopardize patients’ quality of life and increase their financial burden [
12].
It has long been recognized that PD might be linked with multiple comorbidities, like cardiovascular disease, chronic kidney disease, and diabetes [
13,
14]. In terms of PD-related autoimmune diseases, a bidirectional relationship between PD and rheumatoid arthritis was supported by many epidemiological studies [
15]. However, as for SS, this link remains controversial. Several epidemiological studies highlighted that SS patients had a higher risk of developing PD [
16,
17], while patients with PD were also more susceptible to subsequent SS development [
18]. Meanwhile, some key proinflammatory mediators that might drive a higher risk of PD are elevated in saliva extracted from patients with SS, such as IL-12, IL-6, and IL-17, indicating the possible existence of a shared etiopathogenesis among these two diseases [
19‐
22]. Several recent meta-analyses also supported these findings [
23‐
25]. However, there were also some studies reporting no link between PD and SS [
26,
27].
To overcome the restriction and bias of conventional observational studies, including but restricted to measurement error, reverse causality, and residual confounding, an alternative method called Mendelian randomization (MR) has a huge application value in exploring the relationship between PD and SS. MR utilizes exposure/outcome–associated single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) that are distributed during meiosis at random and not subject to reverse causation or residual confounding [
28,
29]. Hence, a bidirectional two-sample MR study was conducted to assess the possible causal association between PD and SS or vice versa by using statistics from the largest genome-wide association studies (GWAS) of PD from the GLIDE consortium and SS from FinnGen consortiums [
30,
31].
Discussion
Up to now, this is the first bidirectional two-sample MR study based on the largest available GWAS to explore the potential causal association between PD and SS. No causal link between PD and SS or vice versa was found on the basis of mendelian randomization assumptions.
Previous researches assessing the relationship between PD and SS seemed very contradictory. Our findings are in line with several previous studies that found no significant association between PD and SS, while those studies solely focused on the possible risk of PD or unfavorable periodontal status among patients with SS without considering whether PD patients have a different likelihood of developing SS versus the general population [
26,
27]. However, there were also several studies in contrast with our results. Two systematic reviews with meta-analysis similarly reported that SS patients were more likely to suffer from PD or worse periodontal status, which was not in line with our results [
23,
25]. However, these two studies still did not examine the risk of developing SS among PD patients, and as kindly figured out by their authors, the reliability of these results was impaired by unsatisfied methodological quality of the primary studies in meta-analysis, high statistical heterogeneity with no explicit source, or selection and cofounding bias in observational studies. Only two studies considered that PD patients might have a different likelihood of developing newly diagnosed SS comparing to the general population, both of which reported that PD patients had higher risk of developing SS [
18,
46]. Another systematic review without meta-analysis further recognized that current evidence about the association between PD and SS or vice versa was still inconclusive [
47]. Possible explanations for the discordance among these observational studies included but are not restricted to potential confounders, such as smoking and other environmental factors, different population settings, and misdiagnosis of early-stage SS with only minor clinical manifestations. These shortcomings in conventional observational studies could lead to significant heterogeneity [
48].
Our study possesses multiple strengths. Initially, this is the first MR research derived from the largest GWAS on both PD and SS currently available, complying with the STROBE-MR statement [
33]. Prudential MR design with the IVW method complemented by four traditional MR methods, CAUSE analysis, and sensitivity analyses has great potential in avoiding reverse causality and residual confounding in traditional observational studies. In addition, there was no evidence for any IV of both PD and SS being correlated to potential confounding factors by searching the PhenoScanner. The IVs in this study are strong enough (F statistic much greater than 10) to diminish potential bias from sample overlap.
Although the MR design gives us a valuable opportunity to explore possible causality between PD and SS, there are still some limitations. Although we tried to extract genetically similar cohorts, the genetical difference between GLIDE consortium on European populations and FinnGen on Finnish samples could introduce bias in our study. However, the GLIDE consortium on the European comprises a subset of participants of European Caucasian ancestry from Finland, which partially intersected with participants from FinnGen database for Sjogren’s syndrome and reduced bias. The subsequent heterogeneity could be further improved by valid measures of the oral disease or endpoint and IVW method with random effects as the major analysis [
49,
50]. Moreover, both two GWAS on PD and SS were derived from individuals of European ancestry, which might cause potential overlap in the exposure and outcome cohorts and hinder the generalizability of our study. To encompass enough SNPs for SS as IV, a more lenient threshold (
P < 5*10
− 5) was applied [
51]. A total of 104 SNPs were extracted for PD as exposure and expressed 12.5% of the variance, while only 6 SNPs were selected for SS as exposure, explaining only 5.01% of the variance. Since 5 of 6 SNPs for SS had low effect allele frequency (< 0.05) (
Table S2), we have to reserve these SNPs instead of deletion. Although a satisfied statistic power (100% to yield an OR of 1.20) was established to explain an impact of PD on SS, a lower power existed in the effect of SS on PD (13% power to yield an OR of 1.20). Inherent heterogeneity was found with the effect of PD on SS, which is likely to influence results. Fortunately, it could be accepted since we utilized IVW method with random effects as the major analysis [
32]. Regarding the interpretation and future practice of our MR analysis, its evidence quality is below that of standard randomized clinical trials (RCTs) and systematic reviews of RCTs according to the evidence-based pyramid [
43,
52]. Last, deidentified GWAS data without specific personal information impeded us from performing a more detailed subgroup analysis based on more specific population settings, where future studies can be improved as the GWAS database expands and is refined.
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