Periodontitis and Breast Cancer: A Bidirectional Two-Sample Mendelian Randomization Study

Research Article

Austin J Cancer Clin Res. 2023; 10(1): 1110.

Periodontitis and Breast Cancer: A Bidirectional Two-Sample Mendelian Randomization Study

Feng KX; Xing ZY; Ren F; Shang QY; Wang X*; Wang X*

Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China

*Corresponding author: Xin Wang & Xiang Wang Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Email: xinwang@vip.126.com; xiangw@vip.sina.com

Received: August 29, 2023 Accepted: September 23, 2023 Published: September 30, 2023

Abstract

Background: Observational studies linking periodontitis and breast cancer may be unreliable due to potential reverse causation and confounders.

Methods: A two-sample bidirectional Mendelian Randomization (MR) analysis was conducted. Techniques such as Inverse-Variance Weighted (IVW) analysis, weighted median, weighted mode, simple mode, and MR-Egger regression were utilized. Sensitivity analyses were also executed.

Results: The IVW results indicated no significant genetic link between periodontitis and increased breast cancer risk (OR=1.01, 95% CI: 0.90-1.13, P=0.92). Four other MR methods concurred. Reverse MR analysis also revealed no association. The IVW findings (OR=1.01, 95% CI: 0.90-1.13, P=0.92) were further validated by four additional MR techniques. As a validation step, periodontitis Genome-Aide Association Study (GWAS) data from the FinnGen consortium and breast cancer GWAS data from UKB were used.

Conclusions: The MR study confirms no bidirectional genetic causality between periodontitis and breast cancer. This aids in understanding the relationship between the two conditions and emphasizes further exploration into how periodontitis might relate to other systemic diseases.

Keywords: Breast cancer; Periodontitis; Mendelian randomization

Abbreviations: GWAS: Genome-Wide Association Study; IVW: Inverse Variance Weighted; MR: Mendelian Randomization; UKB: UK Biobank; SNPs: Single-Nucleotide Polymorphisms; IVs: Instrumental Variables; CI: Confidence Interval; OR: Odds Ratio; R2: Coefficient of Determination; RCT: Randomized Controlled Trial; WM: Weighted Median; EUR-UKB: European Ancestry-UK Biobank.

Introduction

As a public health burden and one of the primary causes of tooth loss, periodontitis is a chronic inflammatory condition with a complex multifactorial etiology [1]. In epidemiological investigations that have previously been performed, periodontal disease has been demonstrated to be causally related to an assortment of systemic illnesses in addition to its local effects, such as cardiovascular disease (Zhou, Dong, Zha, & Liao, 2021), rheumatoid arthritis (Bae & Lee, 2020), Parkinson's Disease (Botelho, Machado, Mendes, & Mascarenhas, 2021), depression (Nolde et al., 2022) and diabetes mellitus (Shah, Schooling, & Borrell, 2021). The investigation of the relationship between periodontal disease and the risk of suffering from cancer has become extremely popular. According to published studies, colorectal, lung, and pancreatic cancers have been associated with the pathogenesis of periodontitis [2-4].

Globally, the risk of contracting breast cancer is the highest among cancers and the second highest in terms of mortality [5]. Numerous risk variables, including endogenous hormone levels, immunological factors, genetic predisposition, and lifestyle choices, have been associated with this cancer according to the data that was accessible. A risk factor for breast cancer has also been associated with periodontal health. Studies that have been published on the possible association between periodontitis and breast cancer have resulted in varying results, with some arguing for a strong association and others arguing against it.

A meta-analysis involving eight studies, 168111 individuals confirmed periodontitis did increase susceptibility to breast cancer (RR=1.18, 95%CI: 1.11-1.26, I2=17.6%) [6]. Freudenheim et al. [7] and Sfreddo et al. [8] reported the same conclusion, while Mai et al. [9], Jia et al. [10], and Han et al. [11] reported different observations. Likewise, breast cancer treatment such as radiotherapy, chemotherapy, and endocrine therapy has an impact on periodontal health [12]. These observational studies are generally limited by residual confounders and reverse causality bias. Therefore, studying the possible causal relationship between periodontitis and breast cancer is a valuable tool to improve the treatment of both diseases.

Mendelian Randomization (MR) is a method based on whole genome sequencing data, similar to randomized controlled trial (RCT) studies, and has developed into a multifaceted approach to assessing causal relationships in epidemiology [13,14]. Using genetic variation closely related to exposure as Instrumental Variables (IVs) to evaluate causality and limit bias due to confounders, MR provides reliable insights into the effects of modifiable exposures on traits of interest, transforming phenotype-to-phenotype causality studies into genotypic studies, compared to traditional observational studies [15,16].

The present study is based on the hypothesis that there may be a bidirectional causal relationship between periodontitis and breast cancer. Therefore, two-sample summary data MR analysis was implemented in the study to investigate the possible bidirectional causal relationship between periodontitis and breast cancer.

Materials and Methods

Data Sources and Selection of Genetic Variants

For the validity of each IV, the Single-Nucleotide Polymorphisms (SNPs) used in MR analyses must fulfil three key assumptions [4]:

(1) Relevance assumption: there is robust association between the instrument and the exposure; (2) Independence assumption: the SNP cannot be related to any confounders of the exposure-outcome association; (3) Exclusion restriction assumption: the SNP has to affect the outcome only through the exposure of interest and not through any other pathway. Figure 1 shows a schematic of the Mendelian randomization study of periodontitis and breast cancer.

We performed the two sample MR analysis on the basis of aggregated statistics from the largest available Genome-Wide Association Study (GWAS) on periodontitis, which included 17353 periodontitis cases and 28210 controls [17]. For breast cancer, the data was from the GWAS including 133384 breast cancer cases and 113789 controls [18]. Both GWAS were performed among people of White European descent. As a validation set, the second data of periodontitis were obtained from the FinnGen consortium R8 release data (3837 cases and 242518 controls) [19,20]. The phenotype “periodontitis” was adopted in the current study. The data of breast cancer was from the UKB (EUR-UKB), including 13879 cases and 198523 controls [21]. The summary of the GWAS included in this Mendelian randomization study was in Table 1.