Folic Acid Intake, Genetic Variations, and DNA Methylation in Hypertensive Disorders of Pregnancy : A Prospective Cohort and Epigenome-Wide Association Study.

AIMS: Research on folate levels in relation to hypertensive disorders of pregnancy (HDP) has yielded inconsistent results, often overlooking the roles of folic acid intake, genetic variations in folate metabolism, and DNA methylation. This study investigates the relationships among these factors and HDP risk.

METHODS

A prospective cohort of 4,079 Chinese pregnant women (2022-2024) assessed the association between folic acid intake, genetic polymorphisms, and red blood cell (RBC) folate metabolites, and gestational hypertension and preeclampsia. An epigenome-wide association study using UK Biobank data (231,057 women) identified folate-linked DNA methylation sites associated with HDP.

RESULTS

Gestational hypertension was observed in 4.8% and preeclampsia in 4.4% of participants. Trajectories of low RBC 5-methyltetrahydrofolate during pregnancy were associated with with a 57% increase in gestational hypertension risk (OR 1.57, 95% CI 1.15-2.15) compared to the median 5-methyltetrahydrofolate group. In contrast, high levels of unmetabolized and intermediary metabolites of folic acid in RBC were linked to a 101% increase in gestational hypertension risk (OR 2.01, 95% CI 1.27-3.17) relative to the low-level group. Pre-pregnancy folic acid intake was associated with elevated levels of 5-methyltetrahydrofolate and unmetabolized/intermediary metabolites, and was linked to a reduced risk of gestational hypertension. Conversely, genetic variants associated with lower levels of 5-methyltetrahydrofolate and higher levels of unmetabolized/intermediary metabolites were linked to an increased risk of gestational hypertension. The epigenome-wide association study identified two folate-related DNA methylation sites associated with HDP: cg16489826 (OR 1.28, 95% CI 1.12-1.47) and cg17054900 (OR 0.86, 95% CI 0.82-0.90).

CONCLUSION

Pre-pregnancy folic acid intake and genetic factors interact to be associated with HDP risk via folate metabolites, with differing relationships observed for 5-methyltetrahydrofolate and unmetabolized/intermediary metabolites in gestational hypertension. Folate-related DNA methylation mechanisms may also be implicated in the risk of HDP.