IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells

Abstract

Genome-wide association (GWA) studies revealed a number of single nucleotide polymorphisms (SNPs) significantly associated with type 1 diabetes (T1D). In an attempt to confirm some of these candidate associations, we genotyped 2046 Caucasian patients and 2417 normal controls from the United States for SNPs in five genomic regions. While no evidence was obtained for four genomic regions (rs2929366/NM_144715 on chromosome 3, rs9127/Q7Z4C4 on chromosome 5, rs1445898/CAPSL on chromosome 5 and rs2302188/NM_033543 on chromosome 19), we provide strong evidence for association between T1D and multiple SNPs in the IFIH1 linkage disequilibrium (LD) block on chromosome 2q. Among the 10 SNPs genotyped for the 2q region, four SNPs located within the IFIH1 gene or at the 5' region of IFIH1 showed significant association with T1D in the Georgia population [odds ratio (OR) = 1.7-1.9] with the best P-value found at SNP rs1990760 (P = 8 x 10(-8) and OR = 1.9). Several SNPs outside of the IFIH1 gene also showed significant but weaker associations. Furthermore, IFIH1 gene expression levels in peripheral blood mononuclear cells are significantly correlated with IFIH1 genotypes, and higher IFIH1 levels are found in individuals with the susceptible genotypes (P = 0.005). Thus, both genetic association and gene expression data suggest that IFIH1 is the most plausible candidate gene implicated in T1D in this LD block.

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

“…(51) suggest that the rs1990760 No significant association with T1DM (58) polymorphism may affect the sequence of the HNF-3b transcription factor binding site in the IFIH1 gene, whereas the rs3747517 polymorphism may alter the binding site for the AP-1 transcription factor. As both polymorphisms are located 45-50kb from the start codon, it has yet to be determined whether these variants really play a role in the regulation of IFIH1 expression or are merely in linkage disequilibrium with a functional polymorphism in this region (42,51). The rs13422767 and rs2111485 polymorphisms are located within the 3' intergenic region adjacent to the IFIH1 gene, 23kb and 13kb from the end of the 3'-UTR of the gene respectively.…”

“…Several IFIH1 polymorphisms were associated with T1DM, with the rs1990760 (G/A) polymorphism, which substitutes an alanine to valine in codon 946 of exon 15, being most strongly associated with protection against development of the disease (odds ratio [OR] = 0.86, P = 1.42 x 10 -10 for the G allele) (50). Associations between IFIH1 polymorphisms and T1DM have been replicated in some populations (29,(51)(52)(53)(54)(55), but not in others (56)(57)(58) (Table 1). Jermendy and cols.…”

“…Interestingly, the G/G genotype of SNP rs1990760 was associated with increased levels of IFIH1 expression in the peripheral blood mononuclear cells of 374 subjects (187 patients with T1DM and 187 nondiabetic controls) (51). The most common homozygous genotypes for the three other polymorphisms of interest were also associated with increased IFIH1 expression, which suggests that increased expression of this gene may be associated with greater susceptibility to T1DM development (51).…”

“…The rs13422767 and rs2111485 polymorphisms are located within the 3' intergenic region adjacent to the IFIH1 gene, 23kb and 13kb from the end of the 3'-UTR of the gene respectively. These polymorphisms do not change any known transcription factor binding sites, and it is not known whether they contribute to the regulation of IFIH1 gene expression (51). Rare va riants, however, are predicted to have significant biological effects on the IFIH1 gene, whether by resulting in a truncated protein product by generating a stop codon in exon 10 (rs35744605), affecting splicing positions (rs35337543 and rs35732034, position +1 of introns 8 and 14 respectively), or changing a highly conserved amino acid (rs35667974 in exon 14) (29).…”

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

“…Higher levels of IFIH1 are found in the PBMCs of individuals with the susceptible polymorphisms of this gene [71]. Additionally, several polymorphisms of this gene have been found to be protective for T1D [72].…”