Genetic Variation in Cardiometabolic Traits and Medication Targets and the Risk of Hypertensive Disorders of Pregnancy

◼ genome-wide association study ◼ genetic predisposition to disease ◼ hypertension, pregnancy-induced H ypertensive disorders of pregnancy (HDPs; eg, gestational hypertension, preeclampsia) are associated with significant maternal and fetal morbidity and mortality.In addition, HDPs are associated with heightened future risk of cardiometabolic risk factors (eg, hypertension, type 2 diabetes mellitus [T2D]) and cardiovascular disease.Whether HDPs reflect latent preceding cardiometabolic risk is unclear.Here, we tested whether genetic predisposition to cardiometabolic traits and variants related to antihypertensive medication targets are associated with HDPs.Analyses used individual-level genomic and phenotypic data from women in the UK Biobank who reported ≥1 live birth.Genetic instruments were constructed from genome-wide association studies external to the UK Biobank, using independent (r 2 <0.2,European 1000Genomes) single-nucleotide polymorphisms (SNPs).Instruments for systolic blood pressure (SBP) and diastolic blood pressure each included 75 SNPs (53 in common). 1 We created genetic instruments for body mass index (BMI; 141 SNPs), 2 resting heart rate (28 SNPs), 3 low-density lipoprotein cholesterol (277 SNPs), 4 T2D (64 SNPs), 5 and ever-smoking (10 SNPs, Tobacco and Genetics Consortium 2010), and genetic proxies for β-blockers (rs11196597, rs1801253, rs4359161), calcium channel blockers (rs7340705, rs2488136, rs1888693, rs16916914, rs10828399, rs10828452, rs12780039, rs11014170, rs7923191, rs12258967, rs1998822, rs4748474, rs2239046), and nitrates (rs13139571, rs3918226, rs891511).Individual-level polygenic risk scores (PRS) were associated with HDPs using multivariable logistic regression, adjusted for enrollment age, the first 20 principal components of ancestry, and genotyping array.The Massachusetts General Hospital institutional review board approved these analyses.Of 214 365 women (mean age, 56.9 years), 2772 (1.29%) had previous HDPs.Women with prior HDP had higher adjusted SBP 1 by 10.53 mm Hg (P<0.001),higher adjusted diastolic blood pressure 1 by 5.97 mm Hg (P<0.001),higher heart rate (71.6 versus 70.4 beats per minute, P<0.001), and higher BMI (28.1 versus 27.1 kg/m 2 , P<0.001); were less likely to have ever smoked tobacco (32.9% versus 40.7%, P<0.001); and were more likely to have T2D (2.3% versus 1.6%, P=0.007).All genetic instruments had F statistics >10 and were strongly associated with corresponding exposures among UK Biobank participants (P<2×10 -16 for all), implying low risk of weak-instrument bias.For both SBP and diastolic blood pressure, the OR for HDP per SD of PRS was 1.22 (P<0.001; Figure A).Associations with SBP PRS were similar in women with gestational hypertension (OR, 1.24 per SD [95% CI, 1.13-1.35])or preeclampsia (OR, 1.19 per SD [95% CI, 1.08-1.31]).Genetic predisposition for increased BMI also increased HDP odds (OR, 1.06 per SD; P=0.004).Blood pressure (BP) and BMI PRS were independent and additive.Genetic predisposition for increased heart rate, T2D, smoking, and low-density lipoprotein cholesterol were not associated