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Cited by 143Diabetes and associated disordersGenetic Associations and EpidemiologyMultiple Sclerosis Research Studies

Genetic Analysis of Adult-Onset Autoimmune Diabetes

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Howson, Joanna M.M., Rosinger, Silke, Smyth, Deborah J., Boehm, Bernhard O., the ADBW-END Study Group, Todd, John A.·2011·Diabetes
DOI 10.2337/db11-0364PMC PMC3178303
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Abstract

OBJECTIVE: In contrast with childhood-onset type 1 diabetes, the genetics of autoimmune diabetes in adults are not well understood. We have therefore investigated the genetics of diabetes diagnosed in adults positive for autoantibodies. RESEARCH DESIGN AND METHODS: GAD autoantibodies (GADAs), insulinoma-associated antigen-2 antibodies (IA-2As), and islet cell autoantibodies were measured at time of diagnosis. Autoantibody-positive diabetic subjects (n = 1,384) and population-based control subjects (n = 2,235) were genotyped at 20 childhood-onset type 1 diabetes loci and FCRL3, GAD2, TCF7L2, and FTO. RESULTS: PTPN22 (1p13.2), STAT4 (2q32.2), CTLA4 (2q33.2), HLA (6p21), IL2RA (10p15.1), INS (11p15.5), ERBB3 (12q13.2), SH2B3 (12q24.12), and CLEC16A (16p13.13) were convincingly associated with autoimmune diabetes in adults (P ≤ 0.002), with consistent directions of effect as reported for pediatric type 1 diabetes. No evidence of an HLA-DRB1*03/HLA-DRB1*04 (DR3/4) genotype effect was obtained (P = 0.55), but it remained highly predisposing (odds ratio 26.22). DR3/4 was associated with a lower age at diagnosis of disease, as was DR4 (P = 4.67 × 10−6) but not DR3. DR3 was associated with GADA positivity (P = 6.03 × 10−6) but absence of IA-2A (P = 3.22 × 10−7). DR4 was associated with IA-2A positivity (P = 5.45 × 10−6). CONCLUSIONS: Our results are consistent with the hypothesis that the genetics of autoimmune diabetes in adults and children are differentiated by only relatively few age-dependent genetic effects. The slower progression toward autoimmune insulin deficiency in adults is probably due to a lower genetic load overall combined with subtle variation in the HLA class II gene associations and autoreactivity.

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  • Compared with childhood-onset type 1 diabetes mellitus, adult-onset disease has a lower frequency of high-risk HLA types, lower concordance rates in twins, more protective genotypes, lower genetic risk scores and lower overall genetic load.

    “Evidence suggests that, compared with childhood-onset T1DM, adult-onset (ages ≥18 years) disease has a lower frequency of high-risk HLA types54, lower concordance rates in twins55, more protective genotypes56, lower genetic risk scores57 and lower overall genetic load (with minor differences in HLA class II gene associations)56.”

    From The epidemiology of type 1 diabetes mellitus in older adults (2025) · cites this paper as [54]

  • A 2011 study of adult-onset type 1 diabetes suggested that autoimmune type 1 diabetes in children and adults differs by just a few age-dependent genetic effects.

    “A 2011 study of adult-onset type 1 diabetes suggested that autoimmune type 1 diabetes in children and adults differs by just a few age-dependent genetic effects;48”

    From Type 1 diabetes (2014) · cites this paper as [48]

  • This mechanism might help explain the differing rates of progression to type 1 diabetes in adults versus children, where only minor variations in genetic susceptibility have been noted.

    “This mechanism might help explain the differing rates of progression to type 1 diabetes in adults versus children, where only minor variations in genetic susceptibility have been noted.48”

    From Type 1 diabetes (2014) · cites this paper as [48]

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Authors
Howson, J. M. M., Rosinger, S., Smyth, D. J., Boehm, B. O., the ADBW-END Study Group, & Todd, J. A.
Affiliations
  • University of Cambridge (GB)
  • Universität Ulm (DE)
Corresponding author
  • Howson, Joanna M.M.
  • the ADBW-END Study Group
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2011-09-16
Volume
60
Issue
10
Pages
2645-2653
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db11-0364
PMC
PMC3178303
OpenAlex
W2152149724
Cited by
143
References
5
Citations by year
2026: 2 · 2025: 8 · 2024: 9 · 2023: 12 · 2022: 8 · 2021: 14 · 2020: 8 · 2019: 10 · 2018: 13 · 2017: 10 · 2016: 11 · 2015: 9 · 2014: 10 · 2013: 9 · 2012: 8
FWCI
5.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Juvenile Diabetes Research Foundation International
  • Wellcome Trust (091157, 079895)
  • National Institute for Health and Care Research (NF-SI-0508-10275)
  • British Heart Foundation (RG/08/014/24067)
  • University of Cambridge
  • Deutsche Forschungsgemeinschaft (SFB518, GrK1041)
  • Cambridge Institute for Medical Research, University of Cambridge (079895)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
glutamic acid decarboxylase antibodies, IA-2 autoantibodies, islet autoantibodies, age at diagnosis, PTPN22, STAT4, CTLA-4, IL2RA, HLA class II
MeSH terms
Adolescent, Adult, Aged, Autoantibodies, Child, Child, Preschool, Diabetes Mellitus, Type 1, Female, Genotype, HLA Antigens, Humans, Infant, Infant, Newborn, Male, Middle Aged, Age Distribution, Genetic Predisposition to Disease, Young Adult

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