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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the French Society of Cardiology, through Fondation Coeur et Recherche (to N.B.-N.); La Federation Francaise de Cardiologie (to N.B.-N.) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at : http://www.nealelab.is/uk-biobank https://broad-ukb-sumstats-us-east-1.s3.amazonaws.com/round2/additive-tsvs/21001\_raw.gwas.imputed\_v3.both\_sexes.tsv.bgz https://broad-ukb-sumstats-us-east-1.s3.amazonaws.com/round2/additive-tsvs/30760\_raw.gwas.imputed\_v3.both\_sexes.varorder.tsv.bgz https://broad-ukb-sumstats-us-east-1.s3.amazonaws.com/round2/additive-tsvs/30780\_raw.gwas.imputed\_v3.both\_sexes.varorder.tsv.bgz https://broad-ukb-sumstats-us-east-1.s3.amazonaws.com/round2/additive-tsvs/30830\_raw.gwas.imputed\_v3.both\_sexes.varorder.tsv.bgz http://ldsc.broadinstitute.org/ldhub/ https://genome.psych.umn.edu/index.php/GSCAN http://www.cerebrovascularportal.org I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript