Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes
Open accessAbstract
Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0–34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3′ end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.
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Up to 90% of individuals with type 1 diabetes diagnosed before age 30 years have the HLA haplotypes DRB1*04-DQA1*03:01-DQB1*03:02 (DR4-DQ8), DRB1*03-DQA1*05:01-DQB1*02:01 (DR3-DQ2.5), or both.
“Up to 90% of individuals with type 1 diabetes diagnosed before age 30 years have the HLA haplotypes DRB1*04-DQA1*03:01-DQB1* 03:02(DR4-DQ8), DRB1*03-DQA1*05:01-DQB1*02:01 (DR3-DQ2.5),or both (379).”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [379]
The Discussion (page not available in our copy) discusses DQ2 and DQ8 haplotypes in patients with type 1 diabetes and relates their disease risk to age at onset. It does not report that up to 90% of people diagnosed before age 30 carry either specified DR–DQ haplotype, or both; that prevalence and age cutoff are unsupported. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe haplotypes DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201, alone or together, may explain up to 90% of type 1 diabetes in children and young adults.
“The HLA DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201 haplotypes, alone or in combination, may account for up to 90% of children and young adults with type 1 diabetes (262).”
From Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus (2011) · cites this paper as [262]
Autoantibodies marking disease pathogenesis are often associated with HLA-DRB1, HLA-DQA1, and HLA-DQB1, suggesting self-peptides may also be presented to T cells.
“Not only the disease but also autoantibodies, which are markers of the disease's pathogenesis, are often associated with HLA-DRB1, HLA-DQA1, and HLA-DQB1, indicating that self-peptides may also be presented to T cells (262).”
From Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus (2011) · cites this paper as [262]
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References 54 · Cited by 230
Research works printed but not linked: 1
- [24]24. Hampel FR, Ronchetti EM, Rousseeuw PJ, Stahel WA: Robust Statistics. New York, Wiley & Sons, 1986
- Authors
- Graham, J., Hagopian, W. A., Kockum, I., Li, L. S., Sanjeevi, C. B., Lowe, R. M., Schaefer, J. B., Zarghami, M., Day, H. L., Landin-Olsson, M., Palmer, J. P., Janer-Villanueva, M., Hood, L., Sundkvist, G., Lernmark, A., Breslow, N., Dahlquist, G., for the Swedish Childhood Diabetes Study Group, Blohmé, G., & for the Diabetes Incidence in Sweden Study Group
- Affiliations
- Simon Fraser University (CA)
- Pacific Northwest Research Institute, Seattle, Washington
- Karolinska Institutet (SE)
- University of Washington (US)
- Department of Medicine, University of Lund, Lund, Sweden
- Institute for Systems Biology, Seattle, Washington
- Institute for Systems Biology (US)
- Department of Endocrinology, University Hospital Malmö, University of Lund, Lund, Sweden
- Department of Medicine, University of Washington, Seattle, Washington
- Umeå University (SE)
- Stockholm South General Hospital (SE)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-05-01
- Volume
- 51
- Issue
- 5
- Pages
- 1346-1355
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2146733470
- Cited by
- 230
- References
- 54
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 10 · 2021: 7 · 2020: 4 · 2019: 9 · 2018: 10 · 2017: 10 · 2016: 10 · 2015: 12 · 2014: 16 · 2013: 13 · 2012: 13
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Novo Nordisk
- National Institutes of Health
- Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK026190)
- 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 › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 1 diabetes, islet autoantibodies, GAD65 antibodies, insulin autoantibodies, HLA-DQ2, HLA-DQ8, INS VNTR, CTLA-4, genetic risk factors, sex differences, immune tolerance induction, disease risk prediction
- MeSH terms
- Adolescent, Adult, Autoantibodies, Child, Child, Preschool, Diabetes Mellitus, Type 1, Female, Genotype, HLA-DQ Antigens, Humans, Infant, Infant, Newborn, Islets of Langerhans, Male, Risk Factors, Biomarkers, Logistic Models, Seroepidemiologic Studies, Age of Onset, Sex Distribution
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