Mendelian randomization (MR) is an analytical approach that uses genetic variants as instrumental variables to estimate the causal effect of exposure on an outcome [1]. This method leverages the principle that genetic variants are randomly assorted during gamete formation and conception, akin to the randomization process in a controlled trial. MR is particularly valuable in epidemiology for inferring causality in observational studies where confounding and reverse causation are significant concerns. The key premise is that genetic variants associated with an exposure of interest are not influenced by confounding factors, thereby providing unbiased estimates of the effect of exposure on the outcome.

Pregnancy-induced hypertension (PIH), also globally known as hypertensive disorders of pregnancy [2], is a prevalent condition occurring during pregnancy. If left undiagnosed and untreated, PIH can result in negative outcomes for both mothers and infants [3]. Additionally, PIH can predispose women to persistent hypertension and cardiovascular problems later in life. Consequently, understanding the pathophysiology of PIH and investigating its preventive measures, along with effective diagnostic and treatment methods, are of paramount importance. The development of biomarkers capable of detecting the PIH risk at an early stage is highly desirable. Factors such as the ratio of placental growth factor (PlGF) to soluble fms-like tyrosine kinase 1 (sFlt-1), 4-hydroxyglutamate, taurine, asparagine, and lipid profiles have been reported to be associated with the pathophysiology of PIH. Nevertheless, traditional observational studies have struggled to establish causal relationships between these factors and the onset of PIH.

In this issue of Hypertension Research, Guo et al. [4] systematically examined potential causal relationships between blood metabolites and the risk of PIH using MR. They employed a two-sample univariable MR approach in their primary analysis, assessed 249 metabolites, and identified 25 metabolites with a causal association with PIH. Among these, 11 were lipid-related traits, and 6 were associated with fatty acid (un)saturation (Fig. 1). By employing Bayesian model averaging MR (MR-BMA), they accounted for pleiotropic effects and evaluated key causal metabolic traits. They identified the total concentration of branched-chain amino acids as the most significant causal metabolite, followed by leucine, the phospholipids to total lipids ratio in medium low-density lipoprotein, and valine. These metabolites have been proposed as potential predictive markers for the onset of PIH and for developing early intervention strategies to mitigate its risk, underscoring the importance of this study.

Investigation of the causal relationship between metabolites and pregnancy-induced hypertension using Mendelian randomization. MR Mendelian randomization, PIH pregnancy-induced hypertension, SM significant metabolite, MR-BMA Bayesian model averaging based Mendelian randomization, LDL low-density lipoprotein

Several studies have suggested a link between unsaturated fatty acids, such as omega-3 and omega-6 fatty acids, and PIH [5,6,7]. However, in this study, the MR-BMA revealed that omega-3 fatty acids, omega-6 fatty acids, or the ratio of omega-6 to omega-3 fatty acids ranked lower in terms of their association with PIH. This suggests that these fatty acids have limited diagnostic or preventive value for PIH. These results are consistent with those of previous studies, indicating that supplementation with unsaturated fatty acids does not significantly decrease the incidence of PIH [8, 9]. This underscores the effectiveness of the MR-BMA method in identifying causal associations. However, several aspects require further investigation. Relationships between the identified metabolites and other factors associated with PIH, such as PlGF, sFlt-1, and 4-hydroxyglutamate, were not examined. Future studies should address these gaps to deepen our understanding of PIH. Nevertheless, this study utilizing MR-BMA is an exceptional investigation that provides comprehensive insights into the causes of PIH. As PIH typically manifests during the second and third trimesters of pregnancy, these findings may inform early intervention strategies to mitigate its risk. Further research is warranted to explore these aspects in greater detail.