Causal Relationship between Gut Microbiota and Endometrial Cancer: A Two-Sample Mendelian Randomization Study

Abstract

Several relevant reports have shown that changes in the composition of the gut microbiota are related to the pathogenesis of endometrial cancer (EC). However, the causal effect of the gut microbiota on EC remains unknown. A two-sample Mendelian randomization (MR) study was used to assess the causal effects of the gut microbiota on EC, EC with endometrioid histologies and EC with non-endometrioid histologies. The genetic statistics of the gut microbiota, including 18,340 participants, were acquired from the MiBioGen database. The summary statistics of EC, EC with endometrioid histologies and EC with non-endometrioid histologies were obtained from the publicly available Genome-wide Association Study (GWAS) database. Suitable single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) (P < 5×10^-8, r² < 0.001). The causal effects were evaluated via the MR-Egger regression method, the inverse-variance weighted (IVW) method, the weighted median test, the weighted mode test, and the simple mode test. The IVW analysis suggested that Ruminococcusgnavusgroup (OR=0.82, 95%CI=0.78-0.85, P=1.29×10^-17), Euryarchaeota (OR=0.90, 95%CI=0.87-0.94, P=3.78×10^-6), and CandidatusSoleaferrea (OR=0.92, 95%CI=0.87-0.98, P=0.01) had protective effects on EC and its subtypes. Gammaproteobacteria (OR=1.29, 95%CI=1.19-1.39, P=2.32×10^-10) served as a risk factor for EC, and Intestinimonas (OR=1.33, 95%CI=1.10-1.62, P=3.68×10^-3) had detrimental effects on EC with non-endometrioid histologies. The causal relationship between the gut microbiota and EC was explored through two-sample MR analysis, which is helpful for further understanding the gut microbiota-mediated development mechanism underlying EC.

Keywords: Mendelian randomization; causality; endometrial cancer; genetics; gut microbiota.

Figure 1

Diagrammatic description of MR analysis. IVW, inverse-variance weighted; PRESSO, Pleiotropy RESidual Sum and Outlier; MR, Mendelian randomization; SNP, single nucleotide polymorphism.

Figure 2

The causality of gut microbiota and EC. (A) The causal effect of Ruminococcusgnavusgroup on EC. (B) The causal effect of Euryarchaeota on EC. (C) The causal effect of CandidatusSoleaferrea on EC. (D) The causal effect of Gammaproteobacteria on EC. (E) The causal effect of Ruminococcusgnavusgroup on ECEH. (F) The causal effect of Euryarchaeota on ECEH. (G) The causal effect of CandidatusSoleaferrea on ECEH. (H) The causal effect of Ruminococcusgnavusgroup on ECNEH. (I) The causal effect of Euryarchaeota on ECNEH. (J) The causal effect of CandidatusSoleaferrea on ECNEH. (K) The causal effect of Intestinimonas on ECNEH. EC, endometrial cancer; ECEH, endometrial cancer with endometrioid histologies; ECNEH, endometrial cancer with non-endometrioid histologies.

Figure 3

The judgment of randomness of Mendel's second Law. (A) Random judgment of MR analysis for SNPs of Ruminococcusgnavusgroup and EC. (B) Random judgment of MR analysis for SNPs of Euryarchaeota and EC. (C) Random judgment of MR analysis for SNPs of CandidatusSoleaferrea and EC. (D) Random judgment of MR analysis for SNPs of Gammaproteobacteria and EC. (E) Random judgment of MR analysis for SNPs of Ruminococcusgnavusgroup and ECEH. (F) Random judgment of MR analysis for SNPs of Euryarchaeota and ECEH. (G) Random judgment of MR analysis for SNPs of CandidatusSoleaferrea and ECEH. (H) Random judgment of MR analysis for SNPs of Ruminococcusgnavusgroup and ECNEH. (I) Random judgment of MR analysis for SNPs of Euryarchaeota and ECNEH. (J) Random judgment of MR analysis for SNPs of CandidatusSoleaferrea and ECNEH. (K) Random judgment of MR analysis for SNPs of Intestinimonas and ECNEH. MR, Mendelian randomization; SNP, single nucleotide polymorphism; EC, endometrial cancer; ECEH, endometrial cancer with endometrioid histologies; ECNEH, endometrial cancer with non-endometrioid histologies.