FURIN Promoter Methylation Predicts the Risk of Incident Diabetes: A Prospective Analysis in the Gusu Cohort

Abstract

BackgroundFurin has been associated with diabetes but the underlying mechanisms are unclear. As a mediator linking fixed genome and dynamic environment, DNA methylation of its coding gene FURIN may be involved. Here, we aimed to examine the prospective association between DNA methylation in FURIN promoter and incident diabetes during 4 years of follow-up in Chinese adults.MethodsDNA methylation levels in FURIN promoter were quantified by target bisulfite sequencing using peripheral blood from 1836 participants in the Gusu cohort who were free of diabetes at baseline. To examine the association between DNA methylation levels in FURIN promoter and incident diabetes, we constructed a logistic regression model adjusting for the conventional factors. Multiple testing was controlled by adjusting for the total number of CpG sites assayed using the false-discovery rate approach.ResultsAmong the 1836 participants free of diabetes at baseline, 109 (5.94%) participants developed diabetes during the average of 4 years of follow-up. Hypermethylation at two of the eight CpG sites assayed in the FURIN promoter was associated with an increased risk of diabetes, after multivariable adjustment and multiple testing correction. Every 5% increment in methylation levels at CpG1 and CpG2 were associated with a 22% (OR=1.22, 95%CI: 1.05-1.43, P=0.009, q=0.038) and 39% (OR=1.39, 95%CI: 1.08-1.77, P=0.009, q=0.038) higher risk of incident diabetes, respectively. The gene-based association analysis revealed that DNA methylation at multiple CpG loci was jointly associated with incident diabetes (P<0.001). Using the average methylation level of the 8 CpG loci in FURIN promoter revealed a similar association (OR=1.28, 95% CI: 1.02–1.62, P=0.037).ConclusionsThese results suggested that the hypermethylation levels in FURIN promoter were associated with an increased risk for incident diabetes in Chinese adults.

An Overview of the Role of Furin in Type 2 Diabetes

“…Such discrepancies need to be taken into consideration and additional research needs to be performed on individuals with different ethnicities and backgrounds. In a different study using the same population, He and colleagues suggested an association between the hypermethylation of the FURIN promoter, which mostly predicts lower furin protein levels and an increased risk of diabetes incidence [52]. As the study mentioned earlier, reduced serum furin levels were also negatively associated with an increased risk of obesity and hypertension which share many risk factors and molecular mechanisms with diabetes [53,54].…”

Functional Roles of Furin in Cardio-Cerebrovascular Diseases

“…65 Similarly to what is seen in hypertension, a study with 4 years of follow up found that nondiabetic individuals with DNA hypermethylation of the promoter region of the FURIN gene might have an increased risk of diabetes (Table 2). 66 Pancreatic β cell dysfunction and insulin resistance might occur if furin is downregulated. Furin is highly expressed in pancreatic islets.…”