Association of HLA-DR, DQ genotype with different beta-cell functions at IDDM diagnosis in Japanese children.
Japanese IDDM patients have been demonstrated to have unique and different HLA associations from white patients. To elucidate the effect of HLA-associated genetic factors on the clinical heterogeneity of IDDM in Japanese people, HLA-DRB1, DQA1, and DQB1 genotypes in 88 childhood-onset Japanese IDDM patients were examined by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) or sequence-specific primers (SSP). Of the 88 IDDM patients, 26 (29.5%) had DRB1*0405-DQA1*0302-DQB1*0401/X (DR4-DQ4/X), 38 (43.2%) had DRB1*0901-DQA1*0302-DQB1*0303/X (DR9-DQ9/X), and 9 (10.2%) were DR4/9-DQ4/9 heterozygous in the present study (X does not contain protective alleles). Clinical heterogeneity such as age distribution at onset, prevalence and serum level of anti-GAD antibodies (GADAb), and residual pancreatic beta-cell function after diagnosis were compared between patients with HLA-DR4-DQ4 and DR9-DQ9. The frequency of DR9-DQ9 genotype was significantly higher in the younger (0-10 years) than in the older (11-16 years) age-group of onset, but the frequency of DR4-DQ4 was higher in the older (11-16 years) age-group. Although no association of DR-DQ genotypes with the prevalence and serum level of GADAb was found among newly diagnosed patients, long-standing DR9-DQ9 patients had significantly higher levels of GADAb than those with DR4-DQ4. While no difference in time course of serum C-peptide (CPR) levels was detected between GADAb+ and GADAb- patients, a remarkable difference was demonstrated between DR9-DQ9 and DR4-DQ4 patients. The residual pancreatic beta-cell function was retained more in patients with DR4-DQ4 than in those with DR9-DQ9 at diagnosis through 12-18 months after diagnosis. These results suggest that the DR9-DQ9 genotype may induce stronger autoimmune destructive response (T-helper 1 function) against target beta-cells than the DR4-DQ4 genotype does. Our findings may warrant further studies on the association of diabetogenic autoimmune response with HLA class II molecules and contribute to a clarification of interracial differences in HLA-encoded susceptibility to IDDM.
Sugihara
S
S
Department of Pediatrics, Chiba University School of Medicine, Japan.
Sakamaki
T
T
Konda
S
S
Murata
A
A
Wataki
K
K
Kobayashi
Y
Y
Minamitani
K
K
Miyamoto
S
S
Sasaki
N
N
Niimi
H
H
D000293:Adolescent; D000367:Age Factors; D017668:Age of Onset; D001323:Autoantibodies / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059810:HLA-DR Serological Subtypes; D015804:HLA-DR4 Antigen / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D007223:Infant; D007328:Insulin / Q000097:blood / Q000378:metabolism* / Q000627:therapeutic use; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism*; D007564:Japan; D016017:Odds Ratio; D016133:Polymerase Chain Reaction
D001323:Autoantibodies; D017931:DNA Primers; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C060029:HLA-DQ4 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; D015804:HLA-DR4 Antigen; C038988:HLA-DR9 antigen; D059811:HLA-DRB1 Chains; D007328:Insulin; D005968:Glutamate Decarboxylase