Human leukocyte antigen identity and DQ risk alleles in autoantibody-positive siblings of children with IDDM are associated with reduced early insulin response. Childhood Diabetes in Finland (DiMe) Study Group.
To investigate the relationship between human leukocyte antigen (HLA)-associated genetic factors and the development of beta-cell dysfunction, we performed sequential intravenous glucose tolerance tests (IVGTTs) on 81 islet cell antibody (ICA)-positive and/or insulin autoantibody-positive healthy siblings of children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). A lower glucose disappearance rate (Kg) (P < 0.5) and decreased first-phase insulin response (FPIR) (P < 0.05) were observed on multiple occasions in HLA-identical siblings compared with the haploidentical or nonidentical ones. Siblings carrying the DQB1*0302/0201, -0302/x, or -0201/x genotype also had lower FPIRs (P < or = 0.05) at several time points than those with no DQB1 risk genotype. When all IVGTTs were taken into account, DQB1*0302/0201 heterozygous siblings had an abnormally low FPIR (< 45 mU/l; 3rd percentile) in at least one test more often than did siblings with no DQB1 risk genotype (50.0% vs. 6.1%; P = 0.001). Siblings carrying either the DQB1*0602 or the DQB1*0603 protective allele had lower serum peak ICA and glutamic acid decarboxylase (GAD)65 antibody levels (P = 0.023 and 0.007, respectively) and higher FPIRs on several occasions (P < 0.05) than those with the DQB1 risk genotypes. Progression to IDDM was related to both HLA identity and the presence of the DQB1*0302/0201 genotype. Normal Kg and FPIR levels were observed in siblings who were positive for only insulin autoantibody, and none of them developed IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Veijola
R
R
Department of Pediatrics, University of Oulu, Finland.
Vähäsalo
P
P
Tuomilehto-Wolf
E
E
Reijonen
H
H
Kulmala
P
P
Ilonen
J
J
Akerblom
H K
HK
Knip
M
M
D000293:Adolescent; D000483:Alleles; D001323:Autoantibodies / Q000097:blood*; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005951:Glucose Tolerance Test; D005968:Glutamate Decarboxylase / Q000276:immunology; D006680:HLA Antigens / Q000097:blood / Q000235:genetics; D006683:HLA-DQ Antigens / Q000097:blood / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006238:Haploidy; D006650:Histocompatibility Testing; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D008297:Male; D009679:Nuclear Family; D011336:Probability; D012307:Risk Factors; D013997:Time Factors
D001323:Autoantibodies; D001786:Blood Glucose; D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D007328:Insulin; C024211:islet cell antibody; D005968:Glutamate Decarboxylase