The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study

Abstract

Background Endometriosis is recognized as a complex gynecological disorder that can cause severe pain and infertility, affecting 6–10% of all reproductive-aged women. Endometriosis is a condition in which endometrial tissue, which normally lines the inside of the uterus, deposits in other tissues. The etiology and pathogenesis of endometriosis remain ambiguous. Despite debates, it is generally agreed that endometriosis is a chronic inflammatory disease, and patients with endometriosis appear to be in a hypercoagulable state. The coagulation system plays important roles in hemostasis and inflammatory responses. Therefore, the purpose of this study is to use publicly available GWAS summary statistics to examine the causal relationship between coagulation factors and the risk of endometriosis. Methods To investigate the causal relationship between coagulation factors and the risk of endometriosis, a two-sample Mendelian randomization (MR) analytic framework was used. A series of quality control procedures were followed in order to select eligible instrumental variables that were strongly associated with the exposures (vWF, ADAMTS13, aPTT, FVIII, FXI, FVII, FX, ETP, PAI-1, protein C, and plasmin). Two independent cohorts of European ancestry with endometriosis GWAS summary statistics were used: UK Biobank (4354 cases and 217,500 controls) and FinnGen (8288 cases and 68,969 controls). We conducted MR analyses separately in the UK Biobank and FinnGen, followed by a meta-analysis. The Cochran’s Q test, MR-Egger intercept test, and leave-one-out sensitivity analyses were used to assess the heterogeneities, horizontal pleiotropy, and stabilities of SNPs in endometriosis. Results Our two-sample MR analysis of 11 coagulation factors in the UK Biobank suggested a reliable causal effect of genetically predicted plasma ADAMTS13 level on decreased endometriosis risk. A negative causal effect of ADAMTS13 and a positive causal effect of vWF on endometriosis were observed in the FinnGen. In the meta-analysis, the causal associations remained significant with a strong effect size. The MR analyses also identified potential causal effects of ADAMTS13 and vWF on different sub-phenotypes of endometrioses. Conclusions Our MR analysis based on GWAS data from large-scale population studies demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis. These findings suggest that these coagulation factors are involved in the development of endometriosis and may represent potential therapeutic targets for the management of this complex disease.

Blood lipids mediate the effects of gut microbiome on endometriosis: a mendelian randomization study

“…One GWAS study has reported that LDL and TC were associated with an increased risk of pulmonary embolism, suggesting the lipids traits were involved in coagulation pathways [ 59 ]. Another MR study has demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis, suggesting the involvement of coagulation factors in endometriosis development [ 60 ].…”

Plasma metabolites and risk of seven cancers: a two-sample Mendelian randomization study among European descendants

“…To assess the robustness of significant association identified by IVW, we conducted a series of complementary and sensitivity analyses, including heterogeneity tests to assess the validity of IVs, Egger intercept test and MR-PRESSO global test to evaluate horizontal pleiotropy, and LOO analyses to examine the presence of dominant IVs [ 37 ]. To examine the possible reverse causality of the identified significant associations, we performed reverse MR analyses in which cancer was treated as the exposure and metabolites as the exposure.…”

Association between periodontitis and endometriosis: a bidirectional Mendelian randomization study

“…Leave-one-out analyses were also utilized to estimate the causality and heterogeneity of the study ( 34 ). As for the pleiotropy analysis, the P -value of the MR-Egger intercept less than 0.05 is considered to suggest the pleiotropy of the study ( 35 ).…”