The association between the IFIH1 locus and type 1 diabetes
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We set out to validate a recently reported type 1 diabetes association from the IFIH1 gene variation in an independent cohort from a population of mixed European descent.
We genotyped five single-nucleotide polymorphisms in the IFIH1 locus, i.e. rs2111485, rs1990760, rs3747517, rs17783344 and rs984971589, in 589 type 1 diabetes nuclear family trios (1,767 individuals).
This study independently replicated the reported genetic association using a family-based approach.
The reported type 1 diabetes association is from a linkage disequilibrium region including three candidate genes, i.e. FAP, IFIH1 and GCA. Further variant discovery and fine mapping could help clarify a novel type 1 diabetes mechanism.
KeywordsAutoimmune disease IFIH1 Genetic susceptibility Genotype Interferon induced with helicase C domain 1 Transmission disequilibrium test Type 1 diabetes Picornavirus infection Single-nucleotide polymorphism Validation
Recently, a large-scale screening of 12,000 non-synonymous single-nucleotide polymorphisms (SNPs) across the human genome  found an association between type 1 diabetes and a non-synonymous SNP (Ala946Thr) at the IFIH1 gene, with the evidence coming from both a case–control approach and a family-based approach. IFIH1 is a putative RNA helicase, upregulated by interferons, especially β-interferon . Ifih1-deficient mice are highly susceptible to picornavirus infection, which suggests that IFIH1 is critical for innate antivirus responses . This is of particular interest given evidence for a role of viral infection in type 1 diabetes . In addition to a proven causal link between type 1 diabetes and congenital rubella , there is evidence suggesting an association with enterovirus and picornavirus infections . Although the genetic effect size found was relatively small [odds ratio (OR) = 0.85], it suggests a potentially important role of innate immunity and interferon responses in the pathogenesis of type 1 diabetes, which may reveal therapeutic targets. The purpose of the current study was to replicate the genetic finding in an independent, family-based Canadian population sample.
In this study, 589 type 1 diabetes nuclear family trios (1,767 individuals) were genotyped. Genomic DNA was obtained after informed consent. The Research Ethics Board of the Montreal Children’s Hospital and other participating centres approved the study. Ethnically, participants were of mixed European descent, with the largest single group being of Quebec French-Canadian origin (40% of total cohort). All patients were diagnosed with type 1 diabetes while younger than 18 years old and had required insulin treatment continuously from the time of diagnosis.
Five SNPs from the IFIH1 locus in this study
3′ flanking of IFIH1
nsSNP (Ala946Thr) of IFIH1
nsSNP (His848Arg) of IFIH1
nsSNP (Ala80Ser) of GCA
3′ flanking of GCA
Genotypes for this study were obtained using the Sequenom iPLEX assay (Sequenom, Cambridge, MA, USA), which has been described in detail in a previous study . The remaining SNPs in the panel were chosen to replicate some candidate-gene findings. One Mendelian error (0.17%) was found in the genotyping of rs2111485; two Mendelian errors (0.34%) were found in the genotyping of rs1990760. None were found in the genotyping of the other three SNPs.
Linkage disequilibrium analyses were performed by Haploview software (http://www.broad.mit.edu/personal/jcbarret/haploview) . Genetic association was tested by the family-based association test software (http://www.biostat.harvard.edu/~fbat/fbat.htm) . Using logistic regression, the OR was estimated based on the transmission disequilibrium test and the UNPHASED software package (http://www.mrc-bsu.cam.ac.uk/personal/frank/software/unphased/) .
Results and discussion
Family-based association tests of the IFIH1 SNPs
Minor allele (frequency)
Hardy–Weinberg p value
Genotyping success rate (%)
Informative family numbera
z value (single-sided p value)
OR (95% CI)b
The type 1 diabetes-associated SNPs, rs2111485 and rs984971, locate in a LD block containing four genes: FAP, IFIH1, GCA and KCNH7 (ESM Fig. 2). The FAP gene product has been identified as a human stromal antigen, which can stimulate cytotoxic T cell responses . The GCA gene product is abundant in neutrophils and macrophages, and is associated with degranulation and consequent immune reaction . Beside the antivirus-related type 1 diabetes mechanism of IFIH1, FAP and GCA may participate in the autoimmune or inflammatory destruction of pancreatic beta cells. Therefore, all of these three genes are candidates for type 1 diabetes. However, further variant discovery and fine mapping are required to confirm that the IFIH1 SNP is actually causative. Because of the tight LD and the small effect size of type 1 diabetes association, this may not be easy. However, if the antivirus-related genetic effect exists, an association between the SNPs and enterovirus infection could be found by a case–control study of host susceptibility. Moreover, if an autoimmune effect were found to exist, association between the SNPs and other cytotoxic autoimmune diseases could be expected, bearing in mind that other autoimmune diseases could also be associated with virus infection. A combined genetic effect of these genes, i.e. antivirus-associated effect and cytotoxic autoimmune reactions, is possible.
This work was funded by the Juvenile Diabetes Research Foundation International and Genome Canada. H.-Q. Qu is supported by a fellowship from the Canadian Institutes of Health Research.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.