title: HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection.
abstract: Recent studies have shown that the risk conferred by the high-risk DQA1*03-DQB1*0302 (DQ8) haplotype is modified by the DRB1*04 allele that is also carried by this haplotype. However, many of these studies suffer from lack of sufficient numbers of DQ-matched control subjects, which are necessary because there is a strong linkage disequilibrium between genes in the HLA complex. In the present study, using a large material of IDDM patients and DQ-matched control subjects, we have addressed the contribution of DR4 subtypes to IDDM susceptibility. Our data, together with recent data from others, clearly demonstrate that some DR4-DQ8 haplotypes are associated with disease susceptibility, while others are associated with protection, depending on the DRB1*04 allele carried by the same haplotype. In particular, our data demonstrate that DRB1*0401 confers a higher risk than DRB1*0404. Based on combined available data on the genetic susceptibility encoded by various DR4-DQ8 haplotypes and the amino acid composition of the involved DRbeta*04 chains as well as the ligand motifs for these DR4 subtypes, we have developed a unifying hypothesis explaining the different risks associated with different DR4-DQ8 haplotypes. We suggest that disease susceptibility is mainly conferred by DQ8 while DR4 subtypes confer different degrees of protection. Some DR4 subtypes (i.e., DRB1*0405, 0402, and 0401) confer little or no protection, while others (i.e., DRB1*0404, 0403, and 0406) cause an increasing degree of protection, possibly by binding a common protective peptide. Features of a protective peptide that fit such a model are briefly discussed.
authors.affiliation: Institute of Transplantation Immunology, The National Hospital, Oslo, Norway. d.e.undlien@rh.uio.no
authors.forename: D E
authors.initials: DE
authors.lastname: Undlien
authors.forename: T
authors.initials: T
authors.lastname: Friede
authors.forename: H G
authors.initials: HG
authors.lastname: Rammensee
authors.forename: G
authors.initials: G
authors.lastname: Joner
authors.forename: K
authors.initials: K
authors.lastname: Dahl-Jørgensen
authors.forename: O
authors.initials: O
authors.lastname: Søvik
authors.forename: H E
authors.initials: HE
authors.lastname: Akselsen
authors.forename: I
authors.initials: I
authors.lastname: Knutsen
authors.forename: K S
authors.initials: KS
authors.lastname: Rønningen
authors.forename: E
authors.initials: E
authors.lastname: Thorsby
mesh_terms: D000293:Adolescent; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D004198:Disease Susceptibility; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D015804:HLA-DR4 Antigen / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D012016:Reference Values; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen