2 SUBSETS OF HLA-DQA1 ALLELES MARK PHENOTYPIC VARIATION IN LEVELS OF INSULIN AUTOANTIBODIES IN FIRST DEGREE RELATIVES AT RISK FOR INSULIN-DEPENDENT DIABETES

Levels of insulin autoantibodies (IAA) vary among different first degr ee relatives of insulin-dependent diabetes mellitus patients, suggesti ng genetic regulation. We previously reported elevated IAA among DR l- positive at risk relatives. In this study, 72/82 at risk relatives wer e IAA positive, of whom 75% (54/72) carried DR4 versus 20% (2/10) of I AA-negative relatives (P = 0.0004). However, 69% (18/26) of DR4-negati ve relatives were IAA positive. Since DR4 did not account for all IAA positivity, we analyzed DQA1 and DQB1 alleles. Homozygosity for DQA1 a lleles deriving from the evolutionary lineage 4 (0401, *0501, *0601) was associated with low IAA levels, while lineage 1-3 alleles (0101, 0102, *0103, *0201, *0301) correlated with higher levels. Most (93%, 65/70) relatives with lineage 1-3 alleles were IAA positive (mean = 36 0+/-63 SERI nU/ml). Only 7/12 relatives homozygous for lineage 4 allel es were IAA-positive, with lower levels than relatives with Lineage 1- 3 alleles (mean = 55+/-15 SEM nU/ml, P < 0.0001; 7/12 vs 65/70, P = 0. 004). The amino acid sequences of lineage 1-3 alleles uniquely share g lutamic acid(E)and phenylalanine(F) at positions 40 and 51 (EF alleles ). Lineage 4 alleles have glycine (G) and leucine (L) at those positio ns (GL alleles). 90% (65/72) of IAA-positive relatives had an EF allel e, while only 75% (54/72) had DR4 (P = 0.01). Homozygosity for GL alle les (often DQA1 0501 on DR3 haplotypes) correlated with little or no humoral response to insulin. Thus, HLA-DQB1 GL alleles, or other genes on haplotypes (e.g., DR3) that carry these DQA1 alleles, may confer r ecessive low responsiveness to insulin.