The IFIH1 gene encodes the pattern recognition receptor MDA5. A common
polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for
autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus
infections are linked to T1D and cause beta-cell damage in vitro. Here
we demonstrate that the rs1990760 polymorphism regulates the interferon
(IFN) signature expressed by human pancreatic islets following
Coxsackievirus infection. A strong IFN signature was associated with
high expression of IFNλ1 and IFNλ2, linking rs1990760 to the expression
of type III IFNs. In the high-responding genotype, IRF-1 expression
correlated with that of type III IFN, suggesting a positive-feedback on
type III IFN transcription. In summary, our study uncovers an influence
of rs1990760 on the canonical effector function of MDA5 in response to
an acute infection of primary human parenchymal cells with a clinically
relevant virus linked to human T1D. It also highlights a previously
unrecognized connection between the rs1990760 polymorphism and the
expression level of type III IFNs.