Calcium homeostasis and endometriosis: A Mendelian randomization study

Background: Previous observational studies have investigated the correlation between calcium homeostasis modulator levels and endometriosis risk. Yet, the genetic association between body calcium homeostasis and endometriosis risk remains to be elucidated. Methods: Four tiers of Mendelian randomization (MR) analysis were conducted, as follows: (1) single univariate MR and (2) multivariate MR to evaluate the correlation between calcium homeostasis regulators and endometriosis; (3) inverse MR to probe the influence of endometriosis on body calcium homeostasis; (4) two-sample MR to scrutinize the connection between calcium levels and endometriosis categories. Results: The two-sample MR analysis unveiled a robust positive correlation between genetically inferred calcium levels and endometriosis risk (IVW: OR = 1.15, 95 % CI: 1.02–1.29, p = 0.018). The MVMR analysis corroborated that the positive correlation of calcium levels with endometriosis persisted after adjusting for 25(OH)D and PTH. The inverse MR analysis disclosed a significant association between endometriosis and 25(OH)D (β = 0.01, 95 % CI: 0.00–0.02, p = 0.007) and calcium (β = 0.02, 95 % CI: 0.00–0.04, p = 0.035). The two-sample MR analysis further demonstrated that calcium levels were positively linked solely to endometriosis of uterus (i.e. adenomyosis, IVW: OR = 1.23, 95 % CI: 1.01–1.49, p = 0.038), with no evidence of a influence on other endometriosis categories. Conclusions: This study, employing various types of MR, offers some genetic evidence for the relationship between calcium homeostasis and endometriosis, augmenting the current comprehension of the complex association between the two and suggesting that calcium levels are a risk factor for endometriosis. These findings provide a unique genetic perspective that may spur further investigation and may inform future strategies for managing patients with endometriosis.