HLA class II alleles specify phenotypes of ketosis-prone diabetes.

Ramaswami Nalini,Ashok Balasubramanyam,Lucille Rodriguez,Mario Maldonado,Christiane S Hampe,Ake Lernmark,Lakshmi K Gaur,Gilberto Garza

doi:10.2337/dc07-1971

Ramaswami Nalini, Ashok Balasubramanyam + Show 6 more

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https://doi.org/10.2337/dc07-1971

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Abstract

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. 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. 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. 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.

Highlights

Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of ␤-cell autoantibodies (Aϩ or AϪ) and ␤-cell functional reserve (␤ϩ or ␤Ϫ)
The frequencies of certain susceptibility (e.g., DQB1*02) and resistance (DQB1*0602) alleles were higher in African-American AϪ␤ϩ KPD patients than in African-American control subjects
Ketosis-prone diabetes (KPD), an emerging form of diabetes defined by presentation with diabetic ketoacidosis (DKA) [1,2,3,4,5,6,7], is phenotypically heterogeneous [1,2,3,4,5,6]

Summary

ORIGINAL ARTICLE

We measured an array of HLA class II alleles at the DQA1, DQB1, and DRB1 loci (including those previously associated with susceptibility or resistance to autoimmune diabetes) in a prospective cohort of KPD patients, analyzed their relationship to the four phenotypes, and compared them with those reported for ethnic-specific normal control populations in Texas by the American Society of Histocompatibility and Immunogenetics (1998) (26 –28). Contingency table analysis with likelihood ratio tests was used to assess frequencies of categorical variables (sex, ethnicity, family history of diabetes, DKA precipitant, proportion of obese patients, ability to discontinue insulin, autoantibody status, ␤-cell functional status, and HLA class II alleles). When this test indicated significant group differences, pairwise comparisons were made. There were significant group differences in HLA class II susceptibility allele frequency (Fig. 1A) due to higher fre-

Nalini and Associates

HLA allele

Allele n Susceptibility

Findings

HLA class II and KPD