HLA class II alleles specify phenotypes of Ketosis-Prone Diabetes (KPD)

Abstract

Objective: Ketosis prone diabetes (KPD) comprises four subgroups based on 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: 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 to those of ethnic-specific population controls.

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 controls (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 controls. DQB1*0302 was more frequent in all KPD subgroups compared to controls.

Conclusions: HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes help specify the four subgroups of KPDM. Inheritance of these alleles may influence long-term β cell functional reserve.