title: Two subsets of HLA-DQA1 alleles mark phenotypic variation in levels of insulin autoantibodies in first degree relatives at risk for insulin-dependent diabetes.
abstract: Levels of insulin autoantibodies (IAA) vary among different first degree relatives of insulin-dependent diabetes mellitus patients, suggesting genetic regulation. We previously reported elevated IAA among DR4-positive at risk relatives. In this study, 72/82 at risk relatives were IAA positive, of whom 75% (54/72) carried DR4 versus 20% (2/10) of IAA-negative relatives (P = 0.0004). However, 69% (18/26) of DR4-negative relatives were IAA positive. Since DR4 did not account for all IAA positivity, we analyzed DQA1 and DQB1 alleles. Homozygosity for DQA1 alleles 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 = 360 +/- 63 SEM nU/ml). Only 7/12 relatives homozygous for lineage 4 alleles 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 glutamic acid (E) and phenylalanine (F) at positions 40 and 51 (EF alleles). Lineage 4 alleles have glycine (G) and leucine (L) at those positions (GL alleles). 90% (65/72) of IAA-positive relatives had an EF allele, while only 75% (54/72) had DR4 (P = 0.01). Homozygosity for GL alleles (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 recessive low responsiveness to insulin.
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver 80262.
authors.forename: A
authors.initials: A
authors.lastname: Pugliese
authors.forename: T
authors.initials: T
authors.lastname: Bugawan
authors.forename: R
authors.initials: R
authors.lastname: Moromisato
authors.forename: Z L
authors.initials: ZL
authors.lastname: Awdeh
authors.forename: C A
authors.initials: CA
authors.lastname: Alper
authors.forename: R A
authors.initials: RA
authors.lastname: Jackson
authors.forename: H A
authors.initials: HA
authors.lastname: Erlich
authors.forename: G S
authors.initials: GS
authors.lastname: Eisenbarth
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D007330:Insulin Antibodies / Q000097:blood*; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D012306:Risk
chemical_list: D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D007330:Insulin Antibodies