Combination of HLA-A24, -DQA1*03, and -DR9 Contributes to Acute-Onset and Early Complete β-Cell Destruction in Type 1 Diabetes

Abstract

To elucidate the genetic factors contributing to heterogeneity of the rate of ␤-cell destruction in type 1 diabetes, we investigated the relationship between the time course of complete ␤-cell loss and HLA class I and II alleles. HLA allele frequencies were also examined among subgroups classified by the mode of onset. The subjects were 266 type 1 diabetic patients (among whom 196 patients were studied longitudinally) and 136 normal control subjects. Earlier complete loss of ␤-cell function was observed in patients who possessed both HLA-A24 and HLA-DQA1*03 and in patients who had HLA-DR9, compared with those without these HLA alleles (P ‫؍‬ 0.0057 and 0.0093, respectively). Much earlier complete ␤-cell loss was observed in the patients who possessed all of HLA-A24, -DQA1*03, and -DR9 compared with the remaining patients (P ‫؍‬ 0.0011). The combination of HLA-A24, -DQA1*03, and -DR9 showed a higher frequency in acute-onset than slow-onset type 1 diabetes (P ‫؍‬ 0.0002). In contrast, HLA-DR2 was associated with a slower rate of progression to complete ␤-cell loss. These results indicate that the combination of HLA-A24, -DQA1*03, and -DR9 contributes to the acute-onset and early complete ␤-cell destruction, whereas HLA-DR2 has a protective effect against complete ␤-cell loss in type 1 diabetes.

Early Onset of Diabetes in the Proband Is the Major Determinant of Risk in HLA DR3-DQ2/DR4-DQ8 Siblings

“…To date, most genetic studies of early-onset diabetes have focused on HLA class I and II, particularly DR3/4-DQ8, A*24:02, B*18:01, and B*39:06 (19,21,22), as well as class I C/natural killer cell receptor interactions (23), yet our study strongly indicates that important factors outside the HLA modulate risk. These are likely to include other genes and potentially other epigenetic and environmental modulators.…”

Prevalence of vitamin D receptor gene polymorphisms FokI and BsmI in Brazilian individuals with type 1 diabetes and their relation to β-cell autoimmunity and to remaining β-cell function

“…Associations between genetic factors such as HLA [37,38], PTNP22 gene [26], and C-peptide levels in T1DM patients have already been described. Petrone et al [37] reported that individuals with high-risk HLA DRB1-DQB1 genotypes had lower C-peptide levels at diagnosis.…”

“…Petrone et al [37] reported that individuals with high-risk HLA DRB1-DQB1 genotypes had lower C-peptide levels at diagnosis. Nakanishi et al [38] described that a combination of HLA class I and class II alleles contributed to ␤-cell destruction in Japanese patients. Recently the PTNP22 1858T gene variant was found to be associated with reduced ␤-cell function in T1DM patients followed by 12 months after diagnosis.…”

Attenuated humoral responses in HLA-A*24-positive individuals at risk of type 1 diabetes

“…HLA-A genotype was determined as HLA-A*24/ HLA-A*24 or HLA-A*24/HLA-A*Y (where Y is any other HLA-A allele). HLA-A*24 four digit typing was not performed since the majority (98%) of people of European descent carry HLA-A*2402 [8]. rs9258750 genotype was determined using a Taqman genotyping assay on the StepOne plus system (Life Technologies, Paisley, UK).…”