HLA Class II Alleles Specify Phenotypes of Ketosis-Prone Diabetes

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Abstract
OBJECTIVE—Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of β-cell autoantibodies (A+ or A−) and β-cell functional reserve (β+ or β−). Genetic factors could contribute to their distinctive phenotypes. Our aim was to specify the role of HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes in determining KPD phenotypes. RESEARCH DESIGN AND METHODS—A total of 185 adults presenting with diabetic ketoacidosis were followed longitudinally for a mean of 5.5 years, with measurements of autoantibodies, β-cell functional reserve, insulin sensitivity, and insulin requirement. Frequencies of susceptibility and resistance alleles at HLA DQA1, DQB1, and DRB1 loci were correlated with clinical and phenotypic features of KPD subgroups and compared with those of ethnic-specific population control subjects. RESULTS—Susceptibility alleles were more frequent (P < 0.0001) in the two A+ than the two A− KPD subgroups; in the latter, the frequency was no greater than in population control subjects (except for DQB1*0302). Susceptibility alleles differentiated the two clinically similar β− subgroups (more frequent in A+β− than A−β− KPD; P < 0.01). Resistance alleles were more frequent in the two β+ than the two β− KPD subgroups (P < 0.01). The frequencies of certain susceptibility (e.g., DQB1*02) and resistance (DQB1*0602) alleles were higher in African-American A−β+ KPD patients than in African-American control subjects. DQB1*0302 was more frequent in all KPD subgroups compared with control subjects. CONCLUSIONS—HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes help specify the four subgroups of KPD. Inheritance of these alleles may influence long-term β-cell functional reserve.