Impacts of HLA-DR3DQ2 and HLA-DR4DQ8 haplotypes singly and combined on autoimmunity, phenotype and comorbidity in patients with Latent Autoimmune Diabetes in the adult. Results from the HUNT and ESTRID studies.

BACKGROUND

The major genetic high-risk of developing autoimmune diabetes are HLA-DR3DQ2 and HLA-DR4DQ8 haplotypes. Their importance in Latent Autoimmune Diabetes in Adults (LADA) has only been partly elucidated. Here we aimed to dissect their impact on autoimmunity, diabetic phenotype, and comorbidity.

METHODS

Data from individuals with LADA were collected from two all-population based surveys, the Norwegian HUNT study (n = 231) and the Swedish ESTRID study (n = 519).

RESULTS

The presence of DR3DQ2 and/or DR4DQ8 HLA-haplotypes augmented disease-associated parameters in LADA compared with the absence of risk haplotypes; this was seen in HUNT and ESTRID alike. Having both risk haplotypes vs. a single risk haplotype increased propensity for high levels of glutamic acid decarboxylase antibody (GADA) in HUNT, with a similar tendency in ESTRID. In HUNT, those with both risk haplotypes displayed higher propensity for treatment with insulin and higher prevalence of hypothyroidism. In ESTRID, the propensity for insulin treatment was more frequent for DR4DQ8 than for DR3DQ2.

CONCLUSION

Presence of a DR3DQ2 or a DR4DQ8 diabetes risk-haplotype associate with different phenotypes of LADA with implications for the known heterogeneity of the disease. In HUNT, but not in ESTRID, the combination of the high-risk haplotypes DR3DQ2 and DR4DQ8 vs. separate high-risk haplotypes associate with enhanced effects on autoimmunity, signs of progression of disease, as well as on comorbidity. Lastly, exploratory findings are consistent with a stronger negative influence by DR4DQ8 than DR3DQ2 as shown in ESTRID. Measurements that include both DR3DQ2 and DR4DQ8 should be relevant when assessing disease progression in LADA patients.