GENETIC AND IMMUNOLOGICAL FINDINGS IN PATIENTS WITH NEWLY-DIAGNOSED INSULIN-DEPENDENT DIABETES-MELLITUS

Two large population-based case-control studies are reviewed. The aim is to determine the effects of HLA, other genetic factors and immune m arkers (ICA, IAA and GAD65Ab) on the age at onset of insulin-dependent diabetes mellitus (IDDM) in 0-34 year olds. The primary HLA risk gene sequence for IDDM was difficult to identify because of the low recomb ination frequency within the HLA region. The frequency of the DR3-DQA1 0501-DQB1*0201 haplotype and the DR3-DQA1*0501-DQB1*0201 (DQ2)/DR4-DQ A10301-DQB1*0302 (DQ8) genotype were higher among patients diagnosed before the age of 10 compared with those diagnosed after the age of 30 . The negatively associated haplotype, DR15-DQA10102-DQB1*0602 was ab sent before the age of 10, but the frequency increased with increasing age at onset. The IDDM2 gene representing the variable number of tand em repeat (VNTR) sequences and 5' of the insulin gene on chromosome 11 were associated with IDDM since homozygous short VNTR was positive bu t not homozygous, and heterozygous long VNTR was negatively associated with the disease. The diagnostic sensitivity and specificity of GAD65 (GA65Ab) and insulin (IAA) autoantibodies varied with the age at onse t and gender. GAD65Ab had the highest sensitivity (> 80%) in patients older than 20 years of age with no difference in gender. The lowest se nsitivity (54%) was in 0-10 year old boys, while age did not affect th e sensitivity in girls. In contrast, the sensitivity of IAA was highes t (46%) before the age of 15 but decreased thereafter as did the sensi tivity for ICA. Classification of patients who develop IDDM above 20-2 5 years of age was inadequate since many patients classified with NIDD M either had GAD65Ab or ICA or developed these antibodies after 1-2 ye ars of NIDDM. We conclude that not only age but also gender affect the risk for IDDM associated with HLA, other IDDM genes as well as common ly used immunological markers for IDDM.