RESUMO
The distribution of DRB1*04 alleles and DRB1/DQB1 haplotypes was analysed in 57 DR4+ caucasoid subjects with insulin-dependent diabetes mellitus (IDDM) and 96 DR4+ healthy controls selected on the basis of DR serology, and the findings were analysed in relation to age at diagnosis of IDDM. DNA samples were amplified using specific DR and DQ primers and hybridized with sequence-specific oligonucleotide probes. A significantly increased combined frequency of DRB1*0401 and 0402 was observed in IDDM subjects aged < or = 12 years at diagnosis (allele frequency 88.4% compared with 62.0% in controls, P < 0.025). There was a non-significant increase in DRB1*0401 and 0402 in IDDM subjects < or = 12 years when compared with IDDM subjects > 12 years (P < 0.1). DRB1*0404 was decreased in the total IDDM subject group compared with controls (4.8% vs. 19.0%, P < 0.025) but did not reach statistical significance in the individual age at diagnosis groups. In contrast, the frequency of DQB1*0302 was increased uniformly across both ages at diagnosis groups. In controls DRB1*0401 occurred in haplotype association with DQB1*0301 in a significantly greater frequency than with DQB1*0302. However, 95.0% of DRB1*0401 IDDM subjects were DQB1*0302. DRB1*0404, which was decreased in frequency in IDDM subjects, occurred in association significantly more frequently with DQB1*0302 in controls. These results imply that DRB1 and DQB1 have independent roles as HLA susceptibility genes in IDDM. DQB1 may have a permissive role whereas DRB1 could influence the rate at which underlying disease progresses to clinical IDDM.
Assuntos
Alelos , Doenças Autoimunes/genética , Diabetes Mellitus Tipo 1/genética , Genes MHC da Classe II , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Adolescente , Adulto , Doenças Autoimunes/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/imunologia , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Cadeias beta de HLA-DQ , Antígeno HLA-DR4/genética , Cadeias HLA-DRB1 , Haplótipos/genética , Humanos , População Branca/genéticaRESUMO
IDDM results from the immune-mediated destruction of pancreatic islet beta cells. Clinicopathologic heterogeneity in IDDM is reflected in part by the wide age range over which the onset of clinical symptoms can occur, after months to years of subclinical "insulitis." Because MHC genes play a critical role in immune function we studied their possible contribution to IDDM heterogeneity by analyzing HLA profiles of 194 IDDM patients in relation to their age at diagnosis. Restriction of HLA-DR heterogeneity was observed in patients diagnosed before age 21 years. Frequencies of DR3 and DR3/4 were highest in the < or = 6-year-old age group and thereafter declined with increasing age at diagnosis. In contrast, the frequency of DR4 remained increased up to age 30 years at diagnosis. DR7, normally considered to be a neutral allele, was like DR2 and DR5, significantly decreased in patients diagnosed before age 21 years. The A30-B18-DR3 haplotype was significantly increased in the < or = 6-year-old age group, A1-B8-DR3 was increased in the > or = 31-year-old group. B62-DR4 was increased only in the > 12-year-old age group. In DR4 patients the frequency of DQ8 was increased across all age groups. A sex difference was observed in those diagnosed at < or = 12 years of age, with an excess of females in the DR3+/DR4- group and males in the DR3-/DR4+ group. An association of DPB1 with IDDM was revealed by an increased frequency overall of DPB1*0301 and/or DPB1*0401, being more pronounced in patients diagnosed at > 20 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)
