Can periodontitis lead to adverse pregnancy outcomes：A Mendelian Randomization study

doi:10.21203/rs.3.rs-3628808/v1

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Can periodontitis lead to adverse pregnancy outcomes：A Mendelian Randomization study

https://doi.org/10.21203/rs.3.rs-3628808/v1

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Objectives

We aim to investigate the potential uni-directional association from periodontitis to the Adverse pregnancy outcomes (APOs) by Mendelian randomization (MR) method.

Materials and Methods

The present study used genetic instruments for periodontitis as exposures. The outcomes included low birthweight (LBW), preterm delivery (PD), preeclampsia or eclampsia (PET) and spontaneous abortion (SAB). The data were collected from the FinnGen consortium R9 datasets and second release analysis in Neale lab of UK Biobank data. Causal analysis uses the inverse variant weighted (IVW), MR Egger and Weighted median methods. A set of sensitivity analyses also be used to test the robustness of the results comprehensive.

Results

The IVW analysis indicate no association of genetically predicted periodontitis will cause the APOs (LBW [IVW OR = 1.003, P = 0.619], PD [IVW OR = 0.984, P = 0.630], PET [IVW OR = 1.005, P = 0.895], SAB [IVW OR = 0.964, P = 0.221]). Results of the other methods did not show significant differences. Sensitivity analyses showed that horizontal pleiotropy could not distort the results of the causal estimation.

Conclusions

The outcomes indicated there was no potential causal effect of periodontitis on APOs.

Clinical Relevance

Mendelian Randomization studies effectively prevent reverse causality and confounding factors. It complements previous studies, thereby informing clinical diagnosis and deepening understanding of periodontitis and systemic diseases.

Periodontitis

Adverse pregnancy outcomes

Mendelian randomization

GWAS

Periodontitis is a chronic multi-factorial inflammatory disease caused by plaque biofilm that result in irreversible destruction of alveolar bone and connective tissue of the tooth[1]. With a high overall prevalence, periodontitis affects 45 to 50 percent of the world's population[2]. Adverse pregnancy outcomes (APOs) covers all pathological pregnancy and childbirth complications, which result in maternal, fetal, and neonatal deaths mainly[3]. Several observational studies have shown that pregnant women with periodontitis have a higher risk of APOs than healthy ones. In 1996, Offenbacher found for the first time that pregnant women with periodontitis had a 7.5 times higher risk of delivering preterm and low-birth-weight babies than healthy women[4]. Subsequent studies have proposed that periodontitis and a sustained immune response may lead to APOs such as low birth weight, preeclampsia, preterm labor[5, 6]. However, a prospective study showed that periodontal conditions in non-smoking pregnant women in the first trimester of pregnancy did not cause preterm labor or low birth weight[7]. Previous studies have been limited by many confounding factors, thus requiring new methods to explore whether periodontitis can lead to APOs.

Mendelian randomization (MR) genetic variation is an effective method using genetic proxies that are specifically related to a particular evaluate to explore the the causal effect between risk factors and the results[8]. Using instrumental variables (IV) to analyze the causal relationship[9], the results will not be affected by confounding and reverse causation. Therefore we conducted a two-sample MR analysis to explore whether periodontitis will cause four most common APOs, including low birthweight (LBW), preterm delivery (PD), preeclampsia or eclampsia (PET) and spontaneous abortion (SAB).

To validly demonstrate a causal effect, the IVs in MR must follow three assumptions[10, 11]: (1) correlation hypothesis: IVs must correlate strongly with exposure; (2) exclusivity hypothesis: IVs must be independent of outcomes; (3) independence hypothesis: IVs be independent of confounding factors. Figure 1 shows a schematic of this Mendelian randomization study.

Data sources

Data of periodontitis, PD, PET and SAB were obtained from the GWAS results on the FinnGen consortium R9 (https://www.finngen.fi/en)[12]. FinnGen Project is lead by the University of Helsinki, and all the study was approved by the ethics committee and institutional review board. According to the Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) definition, comparable standards was used to categorize periodontitis cases[13]. Detailed data in the FinnGen consortium can be found on the FinnGen webpage. The outcome of the birthweight was using data of the weight of the first-born child to measure the LBW from the Neale lab second release analysis of UK Biobank data (http://www.nealelab.is/uk-biobank/). We conducted a two-sample MR study to determine if the periodontitis is the cause factor to APOs using the GWAS summary data on chronic periodontitis (4434 cases and 259,234 controls), PD (8,507 cases and 162,777 controls), PET (7,212 cases and 194,266 controls), SAB (9,113 cases and 89,340 controls), first child birthweight (155,202 cases). All the data were obtained from the samples were all from people of European ancestry (Table S1).

Instrumental variable selection

Ensuring the accuracy of conclusions, we perform the following quality control steps. We control locus-wide significance level (p < 1 × 10^− 5) in selecting instrumental variables (IVs) to obtain a more comprehensive result[14]. Included genetic variants may have potential linkage disequilibrium (LD), we excluded the SNPs by using the PLINK clumping method (r2 > 0.001 and clump window < 10,000 kb) to avoid the impact. During the harmonizing process, we pick out palindromic SNPs to make sure the effects of SNPs equivalent between exposure and outcome. To assess weak instrumental variable bias, we calculated the F-statistics of the IVs that we used. The F-statistic for periodontitis ranged from 19.53 to 27.62, fulfilling the assumption of F > 10 for MR analysis[15].

Mendelian randomization analysis

The two-sample MR analysis perform IVW method, MR Egger and Weighted median method to estimate the causal effect of periodontitis with APOs[16]. And the IVW methd is the primary method for its strong ability to detect causality[17]. Sensitivity analysis was used to ensure the accuracy of the results. The MR-Egger regression was used to confirm the presence of horizontal pleiotropy among the selected SNPs[18]. If horizontal pleiotropy was detected, the analyses were conducted again after excluding the pleiotropy SNPs. Cochran's Q test was performed to evaluate the heterogeneity among SNPs[19]. The effects of a single SNP on the overall estimates were assessed by leave-one-out sensitivity analysis[20]. The strength of the selected IVs was evaluated through the F-statistic to determine whether the estimates of causality were affected by weak instrumental bias. The weak IVs need to be pick out if F statistics < 10[21].All steps were performed by using R package TwoSampleMR in R (version 4.1.2)[22]. For the forest plot drawing, we used the R package Forestplot[23].

After harmonizing the data of periodontitis with APOs, we obtained 25 SNPs of periodontitis as genetic instruments. The IVW analysis result indicated there was no causal inference of periodontitis on four kinds of APOs, as well as in the MR-Egger regression and weighted median methods (Figs. 2 and 3 and Table S2). All the F-statistic values wew greater than 10, and the average value is 21.42 (Table S4). SNPs used as instruments and their association with the outcomes are showed in Table S5.The MR-Egger analysis did not show horizontal pleiotropy (periodontitis on risk of SAB (intercept = -0.01032, P = 0.40747 ), GDM (intercept = 0.00495, P = 0.73047 ), PET (intercept = 0.01901, P = 0.23085 ), PD (intercept = -0.00650, P = 0.64093 ), LBW (intercept = -0.00016, P = 0.95315 ) ) (Table S3). There is no obvious abnormalities in leave-one-out analysis results (Fig. 4). Our results do not support periodontitis is the causal factor to APOs.

Our results showed that there was not a causal inference of genetically defined periodontitis to four types of APOs, which is contradictory to the observational studies before.

The extant studies indicate periodontitis has a prospective effect on the progression of APOs. One study hypothesized that changes in progesterone and estrogen levels during pregnancy would affect the chemotaxis of gingival tissue cells, enzymes, cytokines, and antioxidants, which would contribute to the inflammatory response to gingival tissue and the subgingival microbiota. These changes indirectly lead to increased gingival inflammation[24]. It has also been shown that periodontal disease causes inflammatory mediators such as cytokines or pathogens to enter the amniotic fluid or embryonic tissues through the blood stream[25].However, these phenomena may be the first manifestations of more serious diseases, such as adult cardiovascular and metabolic diseases[26].

Although numerous observational studies have shown that periodontitis during pregnancy can promote the occurrence of low birth weight and premature birth in newborns[5, 6]. But at the same time, many researchers have also observed that periodontitis does not necessarily lead to adverse pregnancy outcomes[7]. Meanwhile, many systematic reviews have found that improving maternal periodontal health does not necessarily improve adverse pregnancy outcomes[27]. We believe that periodontitis may not be the most important cause of adverse pregnancy outcomes, and the occurrence of periodontitis may indicate more serious physical problems. Therefore, GWAS research with larger scale and more accurate classification is more needed.

This study has irreplaceable advantages. First, Mendelian Randomization can simulate randomized control trials to discover the causality, reducing a large amount of time cost, and money. Second, compared with conventional designed observational studies, the genetic potency of the IVs can prevent the effect of reverse causal effect and confounding bias. Third, we perform the first MR analysis focused on the causality between APOs and periodontitis. Considering the high prevalence of periodontitis in the pregnant population worldwide, revealing the causality effect between two diseases is instructive. Fourth, we use four common types of APOs so we can gain more nuanced conclusions.

However, our study also has limitations due to the lack of data. We've only studied the relationship between European populations, so the consistency and scalability among other populations still need to be validated. The other types of the oral diseases should also be focused on. GWAS studies based on inter-age and inter-ethnicity should be continued in the future.

We used Mendelian randomization method for the first time to test the possible role of periodontitis in adverse pregnancy outcomes, and used different testing methods to ensure the accuracy of the results. It was ultimately found that existing research data cannot prove that periodontitis at the genetic level can lead to adverse pregnancy outcomes.

Based on the different MR analysis methods, there is no evidence to support a causal effect on periodontitis to APOs.

Acknowledgements

We want to acknowledge the participants and investigators of the FinnGen study and developers of the R. packages we used in this study.

Declaration or funding

This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

All authors have made substantial contributions to the conception and design of the study. Yan Tianxing was involved in data collection, data analysis and visualization. Wei Yiping were involved drafting the manuscript, and revising it critically. Hu Wennjie was involved in project administration and giving final approval for the version to be published.

Ethics declarations

Ethics approval

FinnGen Project is lead by the University of Helsinki. The relevant study from UK Biobank database is conducted by Neale lab second release analysis. All the study was approved by the ethics committee and institutional review board.

Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data available statement

The summary statistics of the GWAS studies can be found in supplementary material (Table S1).

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Can periodontitis lead to adverse pregnancy outcomes：A Mendelian Randomization study

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