Association between folate deficiency and hypertension: evidence from an observational and Mendelian randomization study.

Aims: Although folate intake might affect hypertension risk, evidence about the risk of hypertension according to an individual's folate deficiency status is scarce. Therefore, we aimed to investigate the relationship between folate deficiency and hypertension, and their causal associations.

Methods and results: A cross-sectional and prospective cohort study were performed in the UK Biobank (UKB) to investigate the associations between folate deficiency and hypertension prevalence and incidence, using logistic regression and Cox proportional hazard regression, respectively. Subsequently, we conducted one-sample Mendelian randomization (MR) with individual-level data from the UKB to further validate their causal associations. Finally, two-sample MR analyses were applied using summary-level data to further assess the causal relationships of serum folate with blood pressure (BP) and hypertension. In a total of up to 219,089 participants free of hypertension at enrollment, 17,670 participants developed hypertension after a median 12.8 years of follow-up. Compared with participants without folate deficiency, those with folate deficiency had a higher risk of hypertension (HR=1.42, 95% CI=1.24-1.63). One-sample MR analysis in the UKB provided supportive evidence for a causal effect of folate deficiency on hypertension risk (OR for the highest quantile=1.07, 95% CI=1.04-1.10, Ptrend<0.001). Furthermore, two-sample MR also supported a protective effect of higher levels of serum folate on BP (For systolic BP: β =-2.313, 95% CI=-3.532, -1.094; for diastolic BP: β = -1.648, 95% CI= -3.085, -0.211) and hypertension (β =-0.049, 95% CI=-0.069, -0.029).

Conclusions: Observational and genetically determined folate deficiency were associated with hypertension, suggesting that folate deficiency might be a causal risk factor for hypertension.