HLA-associated phenotypes in youth with autoimmune diabetes

To examine human leukocyte antigen HLA DRB1-DQB1 haplotypes within a multi-ethnic cohort and assess their association with characteristics of diabetes onset.

The sample included 1662 participants from the SEARCH for Diabetes in Youth Study who tested positive for GADA and/or IA-2A autoantibodies. Blood drawn at the study visit was used to measure fasting C-peptide (FCP) and genotype HLA DRB1 and DQB1 loci. Diabetic ketoacidosis (DKA) at diagnosis was determined from medical records. Multivariable linear and logistic regression models stratified by race/ethnicity were used to assess associations with DRB1-DQB1 haplotypes.

The frequency of DRB1*03 susceptibility haplotypes ranged 27.5-28.9% in all racial/ethnic groups. The frequency of susceptibility DRB1*04-DQB1*0302 was higher in non-Hispanic White (NHW; 34.1%) and Hispanic (38.9%) compared to non-Hispanic Black (NHB; 20.8%) youth. Neutral and protective haplotypes were low frequency in all groups. DBR1*03 haplotypes were associated with younger age at diagnosis in NHW and positivity for multiple autoantibodies in Hispanics. DRB1*04-DQB1*0302 haplotypes were associated with multiple autoantibody positivity in NHW and Hispanics, and lower FCP and higher odds of DKA in Hispanics only. Although protective DRB1*04-DQB1*0301 haplotypes were associated with older age at diagnosis in NHW, they were also associated with multiple autoantibody positivity in these youth. Protective DRB1*13 haplotypes were associated with decreased odds of multiple autoantibody positivity in NHB youth.

The distribution of DRB1-DQB1 haplotypes and their association with onset-related characteristics of autoimmune diabetes varies across major racial/ethnic groups in the USA. This may contribute to variation in clinical presentation of autoimmune diabetes by race/ethnicity.