Abstract 4360714: Insights from RNA-Sequencing and Mendelian Randomization in Endometriosis and Cerebral Small Vessel Disease

Abstract

Background: Endometriosis increases risk of cognitive impairment, coagulopathy, and ischemic and hemorrhagic stroke. Endometriosis affects ~10% of reproductive-age women globally, with little known regarding its link to cerebrovascular disease. Cerebrovascular outcomes in endometriosis overlap with those related to cerebral small vessel disease (CSVD). However, potential biological mechanisms linking endometriosis and CSVD have not yet been explored. Purpose: We assessed transcriptomic and genetic data of menstrual fluid from women with or without endometriosis to identify differentially expressed genes (DEGs) and pathways associated with CSVD. Approach: We analyzed publicly available RNA-sequencing data of menstrual fluid samples from women with (n=11) or without (n=9) endometriosis. DEGs that met Bonferroni-adjusted significance were then selected as exposure variables in Mendelian randomization (MR) analyses. Two-sample MR analyses using publicly available summary statistics from genome-wide association studies. For the exposures, we identified whole-blood expression quantitative trait loci (eQTL, n=943) associated with the significant DEGs selected from the analysis of menstrual fluid samples. The outcomes were derived from summary statistics for three markers of CSVD: white matter hyperintensity volume (WMH, n=18381), perivascular space burden (PVS, n=40095), and cerebral microbleeds (CMB, n=25862). MR analyses were conducted with inverse-weighted variance or Wald ratio methods. Results are presented as odds ratios (OR) and 95% confidence intervals (95%CI). Results: Menstrual fluid of women with or without endometriosis revealed 119 DEGs at a threshold of p<0.05, with 16 meeting corrected statistical significance. All 16 DEGs were upregulated in endometriosis, and associated with ceramide metabolism ( Asah1 , Gla , Hexb ) and lysosome pathways ( Asah1 , Atp6ap1 , Mcoln1 ). MR revealed greater expression of Asah1 was associated with a greater risk of CMBs (OR 1.32, 95%CI: 1.18-1.49, p<0.001). Expression of Zfand5 was associated with greater PVS burden (OR 1.07, 95%CI: 1.01-1.13, p=0.03), though only the Asah1 -CMBs association remained significant after correction for multiple testing. Conclusions: Our findings identify a potential biological pathway linking endometriosis and CSVD. Specifically, involvement of Asah1 may implicate acid ceramidase pathways which have previously been associated with endothelial and microvascular dysfunction.