HLA class II alleles specify phenotypes of ketosis-prone diabetes.
OBJECTIVE
Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of beta-cell autoantibodies (A+ or A-) and beta-cell functional reserve (beta+ or beta-). 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.


METHODS
A total of 185 adults presenting with diabetic ketoacidosis were followed longitudinally for a mean of 5.5 years, with measurements of autoantibodies, beta-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 beta- subgroups (more frequent in A+beta- than A-beta- KPD; P < 0.01). Resistance alleles were more frequent in the two beta+ than the two beta- 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-beta+ 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 beta-cell functional reserve.
Nalini
Ramaswami
R
Translational Metabolism Unit, Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas 77030, USA.
Gaur
Lakshmi K
LK
Maldonado
Mario
M
Hampe
Christiane S
CS
Rodriguez
Lucille
L
Garza
Gilberto
G
Lernmark
Ake
A
Balasubramanyam
Ashok
A
D000328:Adult; D001323:Autoantibodies / Q000097:blood; D016883:Diabetic Ketoacidosis / Q000235:genetics* / Q000276:immunology*; D005006:Ethnicity; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006681:HLA-D Antigens / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D044469:Racial Groups
D001323:Autoantibodies; D006681:HLA-D Antigens