An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes - PubMed (original) (raw)

An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes

Christiane Winkler et al. Diabetes. 2011 Feb.

Abstract

Objective: Genome-wide association studies have identified gene regions associated with the development of type 1 diabetes. The aim of this study was to determine whether these associations are with the development of autoimmunity and/or progression to diabetes.

Research design and methods: Children (n = 1,650) of parents with type 1 diabetes were prospectively followed from birth (median follow-up 10.20 years) for the development of islet autoantibodies, thyroid peroxidase antibodies, tissue transglutaminase antibodies, and diabetes. Genotyping for single-nucleotide polymorphisms of the PTPN22, ERBB3, PTPN2, KIAA0350, CD25, and IFIH1 genes was performed using the MassARRAY system with iPLEX chemistry.

Results: Islet autoantibodies developed in 137 children and diabetes developed in 47 children. Type 1 diabetes risk was associated with the IFIH1 rs2111485 single-nucleotide polymorphism (hazard ratio 2.08; 95% CI 1.16-3.74; P = 0.014). None of the other genes were significantly associated with diabetes development in this cohort. IFIH1 genotypes did not associate with the development of islet autoantibodies (P = 0.80) or autoantibodies against thyroid peroxidase (P = 0.55) and tissue transglutaminase (P = 0.66). Islet autoantibody-positive children with the IFIH1 rs2111485 GG genotype had a faster progression to diabetes (31% within 5 years) than children with the type 1 diabetes protective GA or AA genotypes (11% within 5 years; P = 0.006).

Conclusions: The findings indicate that IFIH1 genotypes influence progression from autoimmunity to diabetes development, consistent with the notion that protective genotypes downregulate responses to environmental insults after initiation of autoimmunity.

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Figures

FIG. 1.

FIG. 1.

Cumulative risk for the development of type 1 diabetes by IFIH1 genotypes. A: Children are grouped with respect to IFIH1 SNP rs2111485 genotype into those carrying GG genotype (solid line) and the GA or AA genotype (dashed line). B: Children are grouped by IFIH1 genotypes after stratification of HLA genotypes (solid and dashed lines are children with TEDDY HLA risk genotypes, and the dotted and dot-dashed lines represent children with low-risk HLA genotypes). P values are provided for comparison of IFIH1 GG vs. GA and AA genotypes in the total cohort (A) and for high-risk (P = 0.03) and low-risk (P = 0.06) genotypes. Follow-up (_x_-axis) is from birth. Numbers below the _x_-axis indicate the number of diabetes-free children remaining on follow-up.

FIG. 2.

FIG. 2.

Cumulative risk for the development of autoantibodies. Cumulative risk is shown for at least one islet autoantibody (A), IAAs (B), GADAs (C), IA-2As (D), ZnT8As (E), TPOAs (F), and tTGAs (G) by IFIH1 genotypes. Children are grouped with respect to IFIH1 SNP rs2111485 genotype into those carrying the GG genotype (solid line) and the GA or AA genotype (dashed line). Follow-up (_x_-axis) is from birth. Numbers below the _x_-axis indicate the number of autoantibody-negative children remaining on follow-up with respect to age.

FIG. 3.

FIG. 3.

Cumulative risk for the progression from islet autoimmunity to type 1 diabetes by IFIH1 genotypes. Islet autoantibody–positive children are grouped with respect to IFIH1 SNP rs2111485 genotype into those carrying the GG genotype (solid line) and the GA or AA genotype (dashed line). Follow-up (_x_-axis) is from the age of the first islet autoantibody–positive sample. Numbers below the _x_-axis indicate the number of diabetes-free children remaining on follow-up.

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