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From Type 1, through LADA, to type 2 diabetes: a continuous spectrum?
1Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Annals of the New York Academy of Sciences
|January 6, 2009
Summary
Genetic analysis reveals a spectrum of HLA-DQ gene variations across diabetes types. Susceptible haplotypes decrease linearly from Type 1 diabetes (T1DM) through Latent Autoimmune Diabetes in adults (LADA) to Type 2 diabetes (T2DM).
Area of Science:
- Immunogenetics
- Endocrinology
- Diabetes Mellitus Research
Background:
- Type 1 diabetes (T1DM), Latent Autoimmune Diabetes in adults (LADA), and Type 2 diabetes (T2DM) represent distinct clinical entities.
- The role of human leukocyte antigen (HLA) genes, particularly HLA-DQ, in the pathogenesis of diabetes is well-established, especially for T1DM.
- Understanding the genetic continuum between these diabetes types may offer new insights into disease mechanisms and classification.
Purpose of the Study:
- To investigate the HLA-DQ genetic background across a spectrum of diabetes mellitus, from T1DM to LADA and T2DM.
- To determine if susceptible and protective HLA-DQ haplotypes exhibit a continuous distribution across these diabetes subtypes.
- To analyze the association of specific HLA-DQA1 and -DQB1 genotypes and haplotypes with different forms of diabetes.
Main Methods:
- Genotyping of HLA-DQA1 and -DQB1 alleles and haplotypes in 223 T1DM, 215 LADA, 206 T2DM patients, and 228 nondiabetic controls.
- Classification of T1DM patients into juvenile-onset (JO) and adult-onset (AO) groups.
- Stratification of LADA patients into LADA1 (GADA titer > 175 U/mL) and LADA2 (GADA titer ≤ 175 U/mL) subgroups.
- Statistical analysis, including linear-by-linear association, to assess frequency trends of specific haplotypes.
Main Results:
- Identified susceptible haplotypes for T1DM: DQA1*03-DQB1*0303, DQA1*03-DQB1*0401, and DQA1*05-DQB1*0201. The protective haplotype was DQA1*0102-DQB1*0602.
- Observed a significant decreasing frequency trend for susceptible haplotypes (DQA1*03-DQB1*0303, DQA1*05-DQB1*0201, DQA1*03-DQB1*0401) from JO T1DM, through AO T1DM, LADA1, LADA2, to T2DM and control groups.
- The frequency of the protective haplotype DQA1*0102-DQB1*0602 showed an increasing trend from T1DM to T2DM and controls.
Conclusions:
- Preliminary data suggest a continuous spectrum of susceptible HLA-DQ haplotypes from T1DM, through LADA, to T2DM.
- These findings support the hypothesis that genetic predisposition, as indicated by HLA-DQ, may bridge the gap between autoimmune and non-autoimmune diabetes forms.
- Further investigation is warranted to confirm and elucidate the implications of this genetic continuum in diabetes mellitus.
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