Dataset Information

Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.

ABSTRACT: Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR?=?1.35, p?=?3.58?×?10-7) with Bonferroni-corrected significance and another known region near PTPN22 (HR?=?1.46, p?=?2.17?×?10-6) and one novel region near PPIL2 (HR?=?2.47, p?=?9.64?×?10-7) with suggestive evidence (p??p?>?2.31?×?10-6). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.

SUBMITTER: Sharma A

PROVIDER: S-EPMC5902429 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.

Sharma Ashok A Liu Xiang X Hadley David D Hagopian William W Chen Wei-Min WM Onengut-Gumuscu Suna S Törn Carina C Steck Andrea K AK Frohnert Brigitte I BI Rewers Marian M Ziegler Anette-G AG Lernmark Åke Å Toppari Jorma J Krischer Jeffrey P JP Akolkar Beena B Rich Stephen S SS She Jin-Xiong JX

Journal of autoimmunity 20180105

Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental D ...[more]

PMID: 29310926

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Project description:Aims/hypothesisWe studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations. Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes.MethodsWe used a risk set sampled nested case-control design within an ongoing international multicentre observational study: The Environmental Determinants of Diabetes in the Young (TEDDY). The TEDDY study followed children with increased genetic risk from birth to endpoints of islet autoantibodies (350 cases, 974 controls) and type 1 diabetes (102 cases, 282 controls) in six clinical centres. Control participants were matched for family history of type 1 diabetes, clinical centre and sex. Plasma ascorbic acid concentration was measured at ages 6 and 12 months and then annually up to age 6 years. SNPs in vitamin C transport genes were genotyped using the ImmunoChip custom microarray. Comparisons were adjusted for HLA genotypes and for background population stratification.ResultsChildhood plasma ascorbic acid (mean ± SD 10.76 ± 3.54 mg/l in controls) was inversely associated with islet autoimmunity risk (adjusted OR 0.96 [95% CI 0.92, 0.99] per +1 mg/l), particularly islet autoimmunity, starting with insulin autoantibodies (OR 0.94 [95% CI 0.88, 0.99]), but not with type 1 diabetes risk (OR 0.93 [95% Cl 0.86, 1.02]). The SLC2A2 rs5400 SNP was associated with increased risk of type 1 diabetes (OR 1.77 [95% CI 1.12, 2.80]), independent of plasma ascorbic acid (OR 0.92 [95% CI 0.84, 1.00]).Conclusions/interpretationHigher plasma ascorbic acid levels may protect against islet autoimmunity in children genetically at risk for type 1 diabetes. Further studies are warranted to confirm these findings.Data availabilityThe datasets generated and analysed during the current study will be made available in the NIDDK Central Repository at https://www.niddkrepository.org/studies/teddy.

Project description:Aims/hypothesisDuring the A/H1N1 2009 (A/California/04/2009) pandemic, mass vaccination with a squalene-containing vaccine, Pandemrix®, was performed in Sweden and Finland. The vaccination was found to cause narcolepsy in children and young adults with the HLA-DQ 6.2 haplotype. The aim of this study was to investigate if exposure to Pandemrix® similarly increased the risk of islet autoimmunity or type 1 diabetes.MethodsIn The Environmental Determinants of Diabetes in the Young (TEDDY) study, children are followed prospectively for the development of islet autoimmunity and type 1 diabetes. In October 2009, when the mass vaccination began, 3401 children at risk for islet autoimmunity and type 1 diabetes were followed in Sweden and Finland. Vaccinations were recorded and autoantibodies against insulin, GAD65 and insulinoma-associated protein 2 were ascertained quarterly before the age of 4 years and semi-annually thereafter.ResultsBy 5 August 2010, 2413 of the 3401 (71%) children observed as at risk for an islet autoantibody or type 1 diabetes on 1 October 2009 had been vaccinated with Pandemrix®. By 31 July 2016, 232 children had at least one islet autoantibody before 10 years of age, 148 had multiple islet autoantibodies and 96 had developed type 1 diabetes. The risk of islet autoimmunity was not increased among vaccinated children. The HR (95% CI) for the appearance of at least one islet autoantibody was 0.75 (0.55, 1.03), at least two autoantibodies was 0.85 (0.57, 1.26) and type 1 diabetes was 0.67 (0.42, 1.07). In Finland, but not in Sweden, vaccinated children had a lower risk of islet autoimmunity (0.47 [0.29, 0.75]), multiple autoantibodies (0.50 [0.28, 0.90]) and type 1 diabetes (0.38 [0.20, 0.72]) compared with those who did not receive Pandemrix®. The analyses were adjusted for confounding factors.Conclusions/interpretationChildren with an increased genetic risk for type 1 diabetes who received the Pandemrix® vaccine during the A/H1N1 2009 pandemic had no increased risk of islet autoimmunity, multiple islet autoantibodies or type 1 diabetes. In Finland, the vaccine was associated with a reduced risk of islet autoimmunity and type 1 diabetes.

Dataset Information

Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.

Publications

Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.

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