Genetics of hypertension-related sex differences and hypertensive disorders of pregnancy

Hypertension and hypertensive disorders of pregnancy (HDP) cause a significant burden of disease on societies and individuals by increasing cardiovascular disease risk. Environmental risk factors alone do not explain the observed sexual dimorphism in lifetime blood pressure (BP) trajectories nor inter-individual variation in HDP risk. In this short review, we focus on the genetics of hypertension-related sex differences and HDP and discuss the importance of genetics utilization for sex-specific hypertension risk prediction. Population and twin studies estimate that 28-66% of variation in BP levels and HDP is explained by genetic variation, while genomic wide association studies suggest that BP traits and HDP partly share a common genetic background. Moreover, environmental and epigenetic regulation of these genes differ by sex and oestrogen receptors in particular are shown to convey cardio- and vasculoprotective effects through epigenetic regulation of DNA. The majority of known genetic variation in hypertension and HDP is polygenic. Polygenic risk scores for BP display stronger associations with hypertension risk in women than in men and are associated with sex-specific age of hypertension onset. Monogenic forms of hypertension are rare and mostly present equally in both sexes. Despite recent genetic discoveries providing new insights into HDP and sex differences in BP traits, further research is needed to elucidate the underlying biology. Emphasis should be placed on demonstrating the added clinical value of these genetic discoveries, which may eventually facilitate genomics-based personalized treatments for hypertension and HDP.