Hypertensive disorders of pregnancy and cardiovascular disease risk: a Mendelian randomisation study

Abstract

Objective: Observational studies show that hypertensive disorders of pregnancy (HDPs) are related to unfavourable maternal cardiovascular disease (CVD) risk profiles later in life. We investigated whether genetic liability to pre-eclampsia/eclampsia and gestational hypertension is associated with CVD risk factors and occurrence of CVD events.

Methods: We obtained genetic associations with HDPs from a genome-wide association study and used individual participant data from the UK Biobank to obtain genetic associations with CVD risk factors and CVD events (defined as myocardial infarction or stroke). In our primary analysis, we applied Mendelian randomisation using inverse-variance weighted regression analysis in ever pregnant women. In sensitivity analyses, we studied men and nulligravidae to investigate genetic liability to HDPs and CVD risk without the ability to experience the underlying phenotype.

Results: Our primary analysis included 221 155 ever pregnant women (mean age 56.8 (SD 7.9) years) with available genetic data. ORs for CVD were 1.20 (1.02 to 1.41) and 1.24 (1.12 to 1.38) per unit increase in the log odds of genetic liability to pre-eclampsia/eclampsia and gestational hypertension, respectively. Furthermore, genetic liability to HDPs was associated with higher levels of systolic and diastolic blood pressure and younger age at hypertension diagnosis. Sensitivity analyses revealed no statistically significant differences when comparing the findings with those of nulligravidae and men.

Conclusions: Genetic liability to HDPs is associated with higher CVD risk, lower blood pressure levels and earlier hypertension diagnosis. Our study suggests similar findings in ever pregnant women, nulligravidae and men, implying biological mechanisms relating to HDPs are causally related to CVD risk.

Keywords: Genetics; Hypertension; Myocardial Infarction; Pregnancy; Stroke.

Figure 1

Mendelian randomisation analysis of genetic liability to pre-eclampsia/eclampsia and risk of cardiovascular events in ever pregnant women. Results are from inverse-variance weighted regression. Models were adjusted for age at baseline and the first 16 genetic principal components. CVD, cardiovascular disease; ICH, intracerebral haemorrhage; MI, myocardial infarction; SAH, subarachnoid haemorrhage.

Figure 2

Mendelian randomisation analysis of genetic liability to gestational hypertension and risk of cardiovascular events in ever pregnant women. Results are from inverse-variance weighted regression. Models were adjusted for age at baseline and the first 16 genetic principal components. CVD, cardiovascular disease; ICH, intracerebral haemorrhage; MI, myocardial infarction; SAH, subarachnoid haemorrhage.

Figure 3

Mendelian randomisation analysis of genetic liability to pre-eclampsia/eclampsia and cardiovascular risk factors in ever pregnant women. *Restricted to individuals not taking lipid-lowering therapy. Results are from inverse-variance weighted regression. Models were adjusted for age at baseline and the first 16 genetic principal components. The variables triglycerides, lipoprotein(a), creatinine, ALAT, ASAT, GGT and C reactive protein were log-transformed. ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; GGT, gamma-glutamyltransferase; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Figure 4

Mendelian randomisation analysis of genetic liability to gestational hypertension and cardiovascular risk factors in ever pregnant women. *Restricted to individuals not taking lipid-lowering therapy. Results are from inverse-variance weighted regression. Models were adjusted for age at baseline and the first 16 genetic principal components. The variables triglycerides, lipoprotein(a), creatinine, ALAT, ASAT, GGT and C reactive protein were log-transformed. ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; GGT, gamma-glutamyltransferase; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein.