Pos0394 the causal relationships between membrane-associated progesterone receptor and osteoporosis: evidence from human studies

Background The observational association has shown that progesterone is associated with osteoporosis (OP)(1), and progesterone was sometimes used as a therapy in osteoporosis treatment [2]. However, controversy over causality remains unresolved[3]. Objectives To reveal the causal association between progesterone and OP. Methods We performed two-sample mendelian randomization (MR) analyses. The summary statistics of membrane-associated progesterone receptor were obtained from the INTERVAL study, which characterized the genetic architecture of 1478 human plasma proteins[4]. The genetic associations of femoral neck bone mineral density (FN-BMD, 32735 samples), forearm bone mineral density (FA-BMD, 8143 samples), lumbar spine bone mineral density ((LS-BMD, 28498 samples), and heel bone mineral density (eBMD, 426824 samples) were obtained from GEnetic Factors for OSteoporosis Consortium (GEFOS)(5) and UK Biobank (containing 426,824 individuals)[6]. The significance threshold was set using independent variants in linkage disequilibrium (r 2 < 0.001) at the standard (p < 5e -6 ) to select single nucleotide polymorphisms (SNPs) as instrumental variables. Inverse variance weighted (IVW), weighted median estimator (WME), and MR-Egger regression methods (MR-ER) were performed in mendelian randomization analysis. Sensitivity analyses were then conducted. The MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) were used to detect and correct the outliers in IVW linear regression[7]. Results MR analyses found that increased level of membrane-associated progesterone receptor was causally linked to decreased FN-BMD (odds ratio =0.95, 95% confidence interval: 0.92-0.99, P =0.0086). No heterogeneity (Q = 9.77, P Q = 0.551) or horizontal pleiotropy (egger regression intercept = -0.008, P = 0.424) was detected. Besides, no significant causation was found between the mineral density of other kinds of bones (FA-BMD, LS-BMD, and eBMD) and progesterone (Figure 1). Conclusion This study support that there are detrimental causal effects of progesterone on OP risk. Further randomized controlled trials are needed to clarify the specific protective mechanisms. References [1]Recker RR, Davies KM, Dowd RM, Heaney RP. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Ann Intern Med. 1999;130(11):897-904. [2]Prior JC. Progesterone for the prevention and treatment of osteoporosis in women. Climacteric. 2018;21(4):366-74. [3]Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol. 1999;94(2):225-8. [4]Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73-9. [5]Zheng HF, Forgetta V, Hsu YH, Estrada K, Rosello-Diez A, Leo PJ, et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015;526(7571):112-7. [6]Morris JA, Kemp JP, Youlten SE, Laurent L, Logan JG, Chai RC, et al. An atlas of genetic influences on osteoporosis in humans and mice. Nat Genet. 2019;51(2):258-66. [7]Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693-8. Figure 1. Forest plot of the results of MR analysis between membrane-associated progesterone receptor and OP. IVW, inverse variance weighted; MR-ER, MR-Egger regression methods; WME, weighted median estimator; OP, osteoporosis; CI, confidence interval; SNP, single nucleotide polymorphisms; FN-BMD, femoral neck bone mineral density; FA-BMD, forearm bone mineral density; LS-BMD, lumbar spine bone mineral density; eBMD, heel bone mineral density. Acknowledgements: NIL. Disclosure of Interests None Declared.