Subject(s)
Arthritis, Juvenile/immunology , HLA Antigens/immunology , Age of Onset , Alleles , Arthritis, Juvenile/genetics , Child, Preschool , HLA-A2 Antigen/immunology , HLA-DP Antigens/genetics , HLA-DP Antigens/immunology , HLA-DP beta-Chains , HLA-DQ Antigens/immunology , HLA-DR Antigens/immunology , HLA-DR Serological Subtypes , HLA-DR5 Antigen/immunology , Humans , Infant , Infant, Newborn , Polymorphism, GeneticABSTRACT
Oligonucleotide typing for alleles of the MHC loci DRB1, DQA1, and DQB1 was performed in 160 patients suffering from EOPA, JCA (or JRA = juvenile rheumatoid arthritis). Allele and haplotype frequencies of the patients were compared with the data of an unrelated healthy control group consisting of 200 individuals. Analysis of frequencies shows that HLA alleles are associated not only with susceptibility to EOPA-JCA but also with protection from the disease. The presence of protection connected with certain HLA alleles was assessed using a calculation which takes into account the condition that if one allele is increased, all other alleles of the same locus must be decreased in compensation. Protection can be assumed only in cases where a given allele has an observed frequency which is significantly beyond the expected compensatory decrease. Thus a hierarchy of associations was observed in EOPA-JCA patients. The alleles of the haplotypes DRB1*11 (12)-DQA1*0501-DQB1*0301 as well as DRB1*08-DQA1*0401-DQB1*0402 were found to be associated with susceptibility to disease, whereas the alleles DRB1*07 and DQA1*0201 converge with significant protection from the disease. Whereas the association with disease susceptibility seems to depend on a sequence motif encoded in certain DQA1 alleles, protection is associated either with alleles of DRB1 or DQA1.
Subject(s)
Alleles , Arthritis, Juvenile/genetics , Arthritis, Juvenile/immunology , HLA-D Antigens/genetics , Haplotypes/genetics , Amino Acid Sequence , Arthritis, Juvenile/pathology , Base Sequence , Child , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Humans , Molecular Sequence DataSubject(s)
Arthritis, Juvenile/immunology , HLA-A2 Antigen/genetics , Histocompatibility Antigens Class II/genetics , Alleles , Base Sequence , DNA Primers/chemistry , Genetic Markers , Genetic Predisposition to Disease , HLA-DP Antigens/genetics , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Humans , Molecular Sequence Data , Polymerase Chain ReactionABSTRACT
We investigated the polymorphic second exon of the HLA-DPB1 and HLA-DRB1 genes, using in vitro DNA amplification by polymerase chain reaction (PCR) and oligonucleotide hybridization in 136 patients with early onset pauciarticular juvenile chronic arthritis (EOPA-JCA) and 199 healthy controls. The analysis of the HLA-DRB1 system revealed that most of the DRB1 alleles are not indifferent with respect to susceptibility to EOPA-JCA. There is a hierarchy of susceptible (DRB1*08, DR5), "permissive" (DRB1*01), moderately "protective" (DR2, DRB1*04), and "protective" (DRB1*07) alleles. In contrast, no hierarchy could be shown for the HLA-DPB1 system. DPB1*0201 was found to be susceptible. The relatively frequent alleles DPB1*0402 and DPB1*0401 seem to be indifferent. The associations with DPB1*0201, DR5, and DRB1*08 are independent of each other: that is to say they, are not brought about by linkage disequilibrium. The susceptible alleles DPB1*0201 and DR5 show evidence for interaction in the pathogenesis of EOPA-JCA. Interaction seems likely between DPB1*0201 and DRB1*08, DR5 and DRB1*08, or between DR6 and DRB1*08. The strongest interaction exists between DPB1*0201 and a common DQ factor associated with both DR5 and DRB1*08. Finally, we observed a hierarchy among the various marker combinations, where the risk of developing EOPA-JCA increases with the number of associated markers present in an individual.
