FURIN promoter methylation predicts the risk of incident hypertension: A prospective analysis of the Gusu cohort

Objectives: Furin has been associated with hypertension through unclear underlying mechanisms. FURIN promoter methylation may participate in the underlying mechanisms, but no evidence supports this possibility. Here, we performed a prospective analysis to study the association between FURIN promoter methylation and incident hypertension. Methods: DNA methylation levels in the FURIN promoter were quantified by target bisulfite sequencing using peripheral blood from 1043 participants in the Gusu cohort (mean age: 50 years, 30% men) who were free of hypertension at baseline. After an average of 4 years of follow-up, 149 (14.3%) participants developed hypertension. Multiple testing was controlled for by measuring the false-discovery rate. Results: Of the eight CpG loci assayed, DNA methylation levels at Chr15: 91416118 were significantly associated with incident hypertension after adjusting for covariates and multiple testing (hazard ratio [HR] = 1.38, 95% confidence interval [CI]: 1.17–1.64, q = 0.001). The weighted truncated-product method, which combines single CpG associations, revealed that DNA methylation at multiple CpG sites was jointly associated with incident hypertension (P < 0.001). Using the average methylation level of all CpG sites as a surrogate for FURIN promoter methylation revealed a similar association (HR = 1.36, 95% CI: 1.08–1.72, P = 0.009). Almost all CpG methylations negatively correlated with serum furin levels, which mediated approximately 29.44% of the association between FURIN promoter methylation and incident hypertension. Conclusions: These results suggest that FURIN promoter hypermethylation is associated with an increased risk for hypertension in Chinese adults, partially through suppressing furin expression or excretion.