RESUMO
The role of the DPB1 gene in genetic susceptibility to type I diabetes has yet to be elucidated. Studies of DPB1 alleles are conflicting. Analysis at the amino acid level, rather than consideration of allelic polymorphism, has been informative in determining disease susceptibility encoded by the DRB1 and DQ genes. In this study, therefore, amino acid variation at polymorphic sites of the DPbeta peptide chain encoded by the second exon of the DPB1 gene was analyzed in diabetic and control subjects from white Caucasian, North Indian Asian, and Jamaican populations. Human leukocyte antigen genotypes and haplotypes were analyzed using a logistic-regression approach and the data were conditioned for the effects on disease risk of the DRB1, DQA1, and DQB1 genes. Eight DPbeta amino acid residues were significantly associated with type I diabetes independent of DR and DQ (DPbeta 9, 33, 35, 36, 55, 56, 57, and 69). None of these residues, however, correlated consistently with disease risk in all three racial groups. This contrasts with findings for the DRbeta, DQalpha and DQbeta peptide chains, where the identity of the amino acid at particular sites has been found to correlate with predisposition to type I diabetes.
Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Antígenos HLA-DP/genética , Alelos , Aminoácidos/análise , Aminoácidos/fisiologia , Frequência do Gene , Ligação Genética , Genótipo , Cadeias beta de HLA-DP , HumanosRESUMO
The association of multiple sclerosis (MS) with the HLA class 11 loci DR and DQ was investigated in populations of Asian Indian and Afro-Caribbean ethnic origin, resident in the United Kingdom. The putative haplotype, DRB1*1501.DQA1*0102.DQBI*0602, was weakly positively associated with MS in both races. The overall contribution to disease susceptibility of this marker was small. Over 80 percent of MS patients in both racial groups did not possess this haplotype. The data suggest that other genetic and/or environmental factors may be more important in predisposing to MS in these two races. Our study also raises the possibility that genetically distinct forms of the disease may be expressed in white Caucasian and non-Caucasian populations (AU)
Assuntos
Humanos , Genes MHC da Classe II/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Esclerose Múltipla/genética , Estudos de Casos e Controles , DNA/sangue , Sondas de DNA de HLA , Antígenos HLA-DQ/classificação , Esclerose Múltipla/etnologia , Reação em Cadeia da Polimerase , Antígenos HLA-DR/classificação , /genética , Reino Unido/epidemiologia , Índia/etnologia , Jamaica/etnologiaRESUMO
Transracial analysis provides a method of distinguishing primary associations between insulin-dependent diabetes mellitus (IDDM) and HLA class II alleles from those secondary to linkage disequilibrium. Blacks show DR-DQ relationships that are different from other races and are a useful group in which to investigate HLA-D region associations with IDDM. In this study, the frequencies of HLA-DQA1 and -DQB1 alleles in Afro-Caribbean IDDM and control subjects were compared. Alleles were identified with sequence-specific oligonucleotide probing. The DQA1 allele A3 was positively associated with IDDM (relative risk[RR] = 25.3, corrected P [Pc]<7.0 x 10 -6). THe DQB1 alleles DQw2 and DQw8 were also positively associated (RR = 4.7, Pc<6.5 x 10 -3 and RR = 12.3,Pc = 3.4 x 10 -3, respectively). The A1.2 and DQw6 alleles were negatively associated (RR = 0.16, Pc<3.5 x 10 -3 and RR = 0.15, Pc = 2.4 x 10 -2, respectively). These findings were compared to data from other races. The positive associations with A3 and DQw2 are consistent with all racial groups investigated. The negative association with DQw6 is present in all racial groups in which it is a common allele. These findings suggest that DQ alleles, and hence DQ molecules, may directly affect predisposition to IDDM. (AU)
Assuntos
Humanos , Alelos , Diabetes Mellitus Tipo 1/genética , Antígenos HLA-DQ/genética , Sequência de Bases , Diabetes Mellitus Tipo 1/imunologia , Suscetibilidade a Doenças/genética , Frequência do Gene , Reino Unido , Jamaica/etnologia , Dados de Sequência Molecular , Sondas de Oligonucleotídeos , Valores de ReferênciaRESUMO
Type 1 (insulin-dependent) diabetic patients and control subjects of Afro-Caribbean Negroid racial origin were investigated by serological HLA-DR-typing and restriction fragment length polymorphism analysis using DNA probes corresponding to the DQO, DQá and DRá chain genes. Combined analysis indicated that four DR antigens are positively associated with the condition in Negroid subjects - DR3, 4, 7 and w9. DR3 and 4 are also associated in Caucasians, but the relative risk for DR3 is lower in Negroid subjects. The DR7 association is specific for the Negroid race, and DRw9 is only weakly associated in Caucasoid subjects. Restriction fragment length polymorphism analysis demonstrated a DQá restriction pattern in Negroid subjects which is absent from Caucasoid subjects. This pattern was associated with DRw9 and a subset of DR7, and was markedly increased in frequency in diabetic patients compared with control subjects (48.7 percent vs 10.4 percent respectively; p<10 -4). In the absence of this pattern, DR7 showed no positive association. DR3 in Negroid subjects was associated with two distinct DQO-DQá patterns, only one of which was positively associated with diabetes. A DQá pattern, in linkage disequilibrium with different DR antigens in different races, conferred a consistent protective effect against the development of Type 1 diabetes. Trans-racial genetic analysis thus supports a primary role for DQ in susceptibility to Type 1 diabetes. (AU)
