Blood pressure, cardiometabolic traits and cardiovascular events in women with uterine fibroids: a genetic correlation and Mendelian randomization study

Abstract

Background. Uterine fibroids (UFs) are under-studied uterus neoplasms, affecting women of reproductive age and often leading to hysterectomy. Clinical series suggest impaired cardiometabolic features including hypertension in UFs. We investigated potential genetic links between blood pressure (BP), several cardiometabolic traits and events and UFs. Methods. We used summary statistics of genome-wide association studies (GWAS) for UFs and 18 traits related to BP and cardio-metabolism. We applied linkage disequilibrium score regression to estimate genetic correlations and GCTA-mtCOJO for adjusted correlations. Univariate and bi-directional Mendelian randomization (MR) were used to test causal associations with UFs. We computed inverse variance-weighted. Weighted median estimation and MR-Egger regression were computed for sensitivity analyses. Multiple testing was addressed by Bonferroni correction. Results. UFs significantly correlated with systolic (rg=0.08, P=8.7x10-5) and diastolic (rg=0.12, P=8.2x10-8) BP, including after adjustment on body mass index (BMI). UFs positively corelated with BMI (rg=0.11, P=4.1x10-4), waist-to-hip ratio (WHR) (rg=0.09, P=7.3x10-3), diabetes (rg=0.15, P=1.9x10-5) and triglycerides (TG) (rg=0.17, P=7.6x10-7). We identified a negative correlation with sex hormone-binding globulin (SHBG) (rg=-0.16, P=3x10-4), a marker of bio-availability of sex-steroids. We found no evidence for shared genetics with vascular diseases, except migraine (rg=0.08, P=5.8x10-7). MR analyses supported BMI, WHR, TG and SHBG, to causally associate with increased risk for UFs. Conclusions. Our study shows that UFs share substantial genetic basis with traits related to BP, obesity, diabetes, in addition to migraine, a predominantly female vascular condition. We provide MR-based evidence for central obesity, visceral fat traits and sex-steroids bio-availability as relevant genetic risk factors for UFs.