Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes

  title={Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes},
  author={Mette Korre Andersen and Maria Sterner and Tom J. Fors{\'e}n and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Olov Rolandsson and Carol M Forsblom and Per-Henrik Groop and Kaj Lahti and Peter M. Nilsson and Leif C. Groop and Tiinamaija Tuomi},
Aims/hypothesisLatent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA).MethodsWe assessed 41 type 2… 

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

The results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus, which is highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.

Etiology and Pathogenesis of Latent Autoimmune Diabetes in Adults (LADA) Compared to Type 2 Diabetes

Data from the limited number of studies on lifestyle factors available indicate that LADA may share several environmental risk factors with type 2 diabetes including overweight, physical inactivity, alcohol consumption (protective) and smoking, suggesting that onset of LADA, similar to type 1 diabetes, to some extent could be prevented or postponed by lifestyle modification such as weight reduction and increased physical activity.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes

The results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies, and observe a novel independent signal at the known type 1 diabetes locus harboring PFKFB3.

Overlap of Genetic Susceptibility to Type 1 Diabetes, Type 2 Diabetes, and Latent Autoimmune Diabetes in Adults

The current status of the understanding of the Genetics of LADA is reviewed and it is placed in the context of what is known about the genetics of its better-studied “cousins,” T1D and T2D, especially with respect to the myriad of discoveries made over the last decade through genome-wide association studies.

TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes

In this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes–linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT.

Genetic Aspects of Latent Autoimmune Diabetes in Adults: A Mini-Review.

Current knowledge of the genetics of LADA is summarized, and the perspectives for future studies are discussed, in order to determine if LADA should be considered as an independent diabetic subtype.

New Insights into the Genetics of Latent Autoimmune Diabetes in Adults

An updated overview of the genetics of LADA is provided, what genetics tell us about LADA as a diabetes subtype is highlighted, and future directions in the study of L ADA point to future directions.

Past, present and future of latent autoimmune diabetes in adults

The recent advancements in LADA epidemiology, clinical features, pathogenesis, and interventions are reviewed and the environmental factors that are thought to play an important role in addition to genetics in the pathogenesis of LADA are highlighted.

Interplay between birthweight, family history, obesity, and genes in the development of latent autoimmune diabetes in adults (LADA) and type 2 diabetes

Results from this thesis indicate that LADA is associated with risk factors linked to insulin resistance and type 2 diabetes while genetic susceptibility is linked foremost to genes associated with autoimmunity and type 1 diabetes.



Genetic Similarities Between Latent Autoimmune Diabetes in Adults, Type 1 Diabetes, and Type 2 Diabetes

LADA shares genetic features with both type 1 (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.

Latent Autoimmune Diabetes in Adults Differs Genetically From Classical Type 1 Diabetes Diagnosed After the Age of 35 Years

LADA patients differed genetically and phenotypically from both T1D>35y and type 2 diabetic patients in a manner dependent on GADA levels, but even the highest quartile differed from type 1 diabetes.

The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study

It is demonstrated that TCF7L2 rs7903146 polymorphism is a population-independent susceptibility locus for LADA in Europeans and the gene effect on diabetes risk may be modulated by BMI, such that the lower the BMI, the higher the geneEffect.

Genetic Analysis of Adult-Onset Autoimmune Diabetes

The 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.

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype

The results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum.

No association of multiple type 2 diabetes loci with type 1 diabetes

The results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.

Association Analysis of Type 2 Diabetes Loci in Type 1 Diabetes

This study suggests that the type 2 diabetes loci do not play any obvious role in type 1 diabetes genetic susceptibility, and the distinct molecular mechanisms of the two diseases highlighted the importance of differentiation diagnosis and different treatment principles.

Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.

GADab+ patients differ from both GADab- type 2 diabetic patients and type 1 diabetic patients with respect to beta-cell function, features of the metabolic syndrome, and type1 diabetes susceptibility genes, and it is proposed that LADA be defined as GADAB positivity (>5 relative units) in patients older than 35 years at onset of type 2 diabetes.

Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects

It is believed that the IL2/IL2R axis represents a potential therapeutic target for delaying the onset of disease and controls both the susceptibility to disease and its time of occurrence.

The islet autoantibody titres: their clinical relevance in latent autoimmune diabetes in adults (LADA) and the classification of diabetes mellitus

A more continuous classification of diabetes mellitus is proposed, based on the finding that the clinical characteristics gradually change from classic Type 1 diabetes to LADA and finally to Type 2 diabetes.