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

Background: Furin 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. Methods: DNA 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. Results: Among 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). Conclusions: These results
suggested that the hypermethylation levels in FURIN promoter were
associated with an increased risk for incident diabetes in Chinese adults.