Abstract 16096: Systolic Blood Pressure, Preeclampsia, and Leiomyoma Genes - A Multivariable Mendelian Randomization and Mediation Analysis

Abstract

Introduction: Preeclampsia (PE) (sudden-onset hypertension (>20 weeks gestation) with proteinuria, maternal organ/uteroplacental dysfunction or angiogenic imbalance) affects ~4 million women annually, causing death of >70,000 women and 500,000 babies, and sequelae like heart failure. Hypothesis: We hypothesize that among the known genetic associations of PE is an independent risk factor (IRF). Methods: Data Publicly available European ancestry genome-wide association study (GWAS) summary statistics (SS) derived single nucleotide polymorphism (SNP) based genetic instruments ( P- value≤5x10 -08 , r 2 <0.001) for known associations of PE [body mass index (BMI, kg/m 2 ) (339,224 subjects), high density lipoprotein (HDL, mg/dl) (188,577), blood pressure BP (mm Hg) - systolic (S) and diastolic (D) (458,577)] with SS for PE or eclampsia (7212 cases, 194266 controls) (outcome). Analyses 1) univariate two-sample Mendelian randomization (MR) [inverse variance weighted method (IVWM) for results; MR-Egger, and weighted-median methods for sensitivity analyses]; 2) multivariable (MV) MR to identify IRF after MV adjustment, 3) quantify change in effect size of IRF after adjustment (results reported as odds of PE per 10 unit change in SBP/DBP/HDL, and per standard deviation (SD) change in BMI); and 4) FUMA based analysis of IRF SNPs to annotate uterine genes using GTEx v8. Results: In 1) IVWM analysis, SBP (OR= 2.23 [95% CI= 1.82, 2.72]), DBP (3.32 [2.46,4.48], HDL (0.22 [0.09,0.55]), and BMI (1.58 [1.34,1.86]) associated with the odds of a diagnosis of PE; 2) MVMR analysis, only SBP (1.82 [1.11, 3.00] remained significant, after adjustment for BMI, DBP, and HDL; 3) proportion-explained analysis, ~18% reduction in the OR of SBP, after adjustment for BMI, DBP, and HDL; and 4) in FUMA based analyses, out of 7 gene associations, the top 2 uterine genes for SBP SNPs were ZNF859 , and CDC25A . Conclusions: Genetic predisposition to elevated SBP associated with increased odds of PE, independent of BMI, DBP, and HDL. Adjustment attenuated risk, suggesting shared genetic mechanisms. SBP is an independent risk factor for PE. SBP SNPs map to uterine ZNF859 and CDC25A, known leiomyoma associated genes, suggesting a pleiotropic role in PE development.