ArticleDiabetologia2008
Joint effects of HLA, INS, PTPN22 and CTLA4 genes on the risk of type 1 diabetes.
Article in Diabetologia, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 59 citations in OpenAlex.
- Type 1 Diabetes Mellitus Pathogenesis: Mechanisms, Early Diagnostic Strategies, and Emerging Therapeutic Approaches.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026Review
- The Impact of Maternal Obesity and Diabetes on the Development of Congenital Heart Defects (CHDs) in Offspring: A Narrative Review.Metabolites · 2026Review
- Immunomodulatory agents and cell therapy for patients with type 1 diabetes.Archives of endocrinology and metabolism · 2025Review
- Genetic Discovery and Risk Prediction for Type 1 Diabetes in Individuals Without High-Risk HLA-DR3/DR4 Haplotypes.Diabetes care · 2025Article
- Deep integrative models for large-scale human genomics.Nucleic acids research · 2023Article
- CTLA4, SH2B3, and CLEC16A diversely affect the progression of early islet autoimmunity in relatives of Type 1 diabetes patients.Clinical and experimental immunology · 2023Article
- The missing heritability in type 1 diabetes.Diabetes, obesity & metabolism · 2022Review
- Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects.Frontiers in immunology · 2022Article
- Type 1 Diabetes and Autoimmune Thyroid Disease-The Genetic Link.Frontiers in endocrinology · 2021Review
- Variants in the BACH2 and CLEC16A gene might be associated with susceptibility to insulin-triggered type 1 diabetes.Journal of diabetes investigation · 2019Article
- Early prediction of autoimmune (type 1) diabetes.Diabetologia · 2017Review
- GCORE-sib: An efficient gene-gene interaction tool for genome-wide association studies based on discordant sib pairs.BMC bioinformatics · 2016Article
- Saffold Virus, a Human Cardiovirus, and Risk of Persistent Islet Autoantibodies in the Longitudinal Birth Cohort Study MIDIA.PloS one · 2015Article
- Improving prediction of type 1 diabetes by testing non-HLA genetic variants in addition to HLA markers.Pediatric diabetes · 2014Article
- Pathogenesis of type 1 diabetes: lessons from natural history studies of high-risk individuals.Annals of the New York Academy of Sciences · 2013Review
- Assessment of type 1 diabetes risk conferred by HLA-DRB1, INS-VNTR and PTPN22 genes using the Bayesian network approach.PloS one · 2013Article
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- Improving power of genome-wide association studies with weighted false discovery rate control and prioritized subset analysis.PloS one · 2012Article
- HLA-DQ haplotypes differ by ethnicity in patients with childhood-onset diabetes.Pediatric diabetes · 2011Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background/hypothesisHLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes.
methodsWe genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, -DQA1 and -DQB1, the insulin gene (INS, -23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp).
resultsThe joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene-gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference).
conclusionMost established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally.
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