DRB1-ASTERISK-0403 PROTECTS AGAINST IDDM IN CAUCASIANS WITH THE HIGH-RISK HETEROZYGOUS DQA1-ASTERISK-0301-DQB1-ASTERISK-0302 DQA1-ASTERISK-0501-DQB1-ASTERISK-0201 GENOTYPE/

The human leukocyte antigen (HLA) class II genotype DQA10301-DQB1*030 2/DQA10501-DQB1*0201 has been identified as a marker strongly predisp osing to insulin-dependent diabetes mellitus (IDDM) in Caucasian popul ations. Its frequency in control populations (1-3%) is still, however, 1 order of magnitude higher than the prevalence of IDDM, suggesting t hat its penetrance can be modified by protective factors, In this stud y we searched for such a factor in the DRB1 locus by studying DRB104 polymorphism in 174 European Caucasian IDDM patients and 73 nondiabeti c control subjects, all sharing the HLA-DR3/DR4 phenotype. Significant protection was encoded by the DRB10403 allele, which was observed in 5 of 49 control subjects (10%) and none of 171 IDDM patients (0%) wit h the DQA10301-DQB1* 0302/DQA1*0501-DQB1*0201 genotype (RR = 0.02 [0. 01-0.18], P < 0.0005), These data support the concept that protective HLA class II genes can overrule the risk caused by HLA-DQ susceptibili ty dimers, They also contribute to a possible strategy to screen for n ondiabetic individuals with increased genetic risk of developing IDDM.