Predictive value of human leukocyte antigen class II typing for the development of islet autoantibodies and insulin-dependent diabetes postpartum in women with gestational diabetes

Gestational diabetes mellitus (GDM) is a risk factor for the development of insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabet es mellitus postpartum. To evaluate whether there is any association of hum an leukocyte antigen (HLA) class II alleles (DR and DQ) with GDM and the po stpartum development of IDDM, we analyzed 184 women with GDM from Germany f or HLA class II alleles, islet autoantibodies [islet cell autoantibodies (I CA), glutamic acid decarboxylase autoantibodies (GADA), and protein tyrosin e phosphatase IA-2 autoantibodies (IA-2A), and the postpartum development o f diabetes. No elevation in the frequency of any HLA class II alleles was o bserved in GDM patients compared to 254 non-diabetic unrelated subjects. DR 3 allele frequency was significantly increased in 43 women with islet autoa ntibodies [corrected P value (P-c) = 0.02], in particular in those with GAD A (P-c = 0.002), or in the 24 women who developed IDDM postpartum (P-c = 0. 005). In women with GADA, DR4 and DQB1*0302 were significantly elevated (P- c = 0.009). Twenty-five (59.5%) islet antibody-positive women and 17 (74%) women who developed IDDM postpartum had a DR3- or DR4-containing genotype. The cumulative risk to develop IDDM within 2 yr postpartum in GDM women wit h either DR3 or DR4 was 22% compared to 7% in women without those alleles ( P = 0.02) and rose to 50% in the DR3- or DR4-positive women who had require d insulin during pregnancy (P = 0.006). Combining the determination of susc eptible HLA alleles (DR3, DR4) with islet autoantibody measurement increase d the sensitivity of identifying GDM women developing postpartum IDDM to 92 %, but did not improve risk assessment above that achieved using GADA measu rement alone, which was the strongest predictor of IDDM. These results indi cate that women with GDM who have islet autoantibodies at delivery or devel op IDDM postpartum have HLA alleles typical of late-onset type 1 diabetes, and that both HLA typing and islet antibodies can predict the development o f postpartum IDDM.