Causal effects of glycemic traits and endometriosis: a bidirectional and multivariate mendelian randomization study

Abstract

Background: Observational studies have suggested an association between endometriosis and glycemic traits, but causality remains unclear. We used bidirectional and multivariate Mendelian randomization (MR) to examine the causal effect of glycemic traits on endometriosis and vice versa.

Methods: We obtained genome-wide association studies summary data of endometriosis and glycemic traits in our study. Inverse variance weighted (IVW), Weighted median, MR-Egger and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were applied in bidirectional two-sample MR analyses. MVMR was implemented to estimate the causal effect for fasting insulin (FI), fasting glucose (FG), and glycosylated hemoglobin A1c (HbA1c) on endometriosis. To test the validity of our findings, a number of sensitivity analyses were conducted.

Results: The risk of endometriosis was significantly increased by genetically predicted T1DM (OR = 1.02, 95% CI 1.00-1.04, p = 0.0171, q = 0.0556) and GDM (OR = 1.01, 95% CI 1.01-1.02, p = 1.34 × 10^{- 8}, q = 1.74 × 10^{- 7}). Endometriosis had a suggestive association with HbA1c (Beta = 0.04, 95% CI 0.00-0.08, p = 0.0481, q = 0.1251). Using multivariate Mendelian randomization (MVMR), a significant causal effect of FI on genetically predicted endometriosis was found (OR = 2.18, 95% CI 1.16-4.09, p = 0.0154, q = 0.0547). Moreover, no causal associations between endometriosis and other glycemic traits were detected.

Conclusion: Our findings supported the significant causal associations of T1DM, GDM and FI with endometriosis, respectively. Additionally, a suggestive association was found of endometriosis on HbA1c. Importantly, our study may shed light on etiology studies and clinical management of endometriosis.

Keywords: Diabetes; Endometriosis; Glycemic traits; Mendelian randomization.

Fig. 1

The overall workflow of the study T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; GDM, Gestational diabetes mellitus; FI, Fasting insulin; FG, Fasting glucose; HbA1c, Hemoglobin A1c

Fig. 2

Association of glycemic traits and endometriosis in UVMR analyses ^aAfter removing outliers from MR-PRESSO outlier test. The ORs in this study show the impact of per log-OR rise in glycemic traits on endometriosis (a) and vice versa (b). These ORs were derived from an inverse-variance weighted technique. T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; GDM, Gestational diabetes mellitus; FI, Fasting insulin; FG, Fasting glucose; HbA1c, Hemoglobin A1c

Fig. 3

Scatter plots of UVMR (a) for T1DM on endometriosis; (b) for T2DM on endometriosis; (c) for GDM on endometriosis; (d) for FI on endometriosis; (e) for FG on endometriosis; (f) for HbA1c on endometriosis; (g) for endometriosis on T1DM; (h) for endometriosis on T2DM; (i) for endometriosis on GDM; (j) for endometriosis on FI; (k) for endometriosis on HbA1c. For each SNP, the 95% confidence intervals are shown by the lines that are horizontal and vertical. The correlations’ strength, which was calculated using various methods, is indicated by the solid lines’ slopes. T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; GDM, Gestational diabetes mellitus; FI, Fasting insulin; FG, Fasting glucose; HbA1c, Hemoglobin A1c