title: DR4 subtypes and their molecular properties in a population-based study of Swedish childhood diabetes.
abstract: The aim of this study was to determine the association between childhood insulin-dependent diabetes mellitus (IDDM) and HLA-DR4 subtypes and to test in a population-based investigation whether the DR4 association has an effect independent to that of DQ. First, HLA genotyping identified DR4 in 337/425 (79%) patients and 148/367 (40%) controls (Odds Ratio 5.67; p < 0.01). Second, a total of 14 DR4 subtypes were detected by PCR and sequence specific oligo probes. Only two DR4 subtypes, DRB1*0401 (62% patients and 25% controls; OR 4.95, p < 0.01) and *0404 (16% patients and 10% controls; OR 1.67, p < 0.05) were however positively associated with the disease. These two subtypes were positively associated only when linked to DQB1*0302-DQA1*0301 (DQ8) (56% patients and 14% controls; OR 7.69, p < 0.01; 15% patients and 10% controls; OR 1.55, p < 0.05, respectively). When DRB1*0401 was linked to DQB1*0301-DQA1*0301 (DQ7) (6% patients and 11% controls; OR 0.52, p < 0.05), this DR4 subtypes was negatively associated with IDDM. Third, tests of strongest association allowed the following ranking of alleles or haplotypes DQB1*0302-DQA1*0301 (DQ8) > DQB1*0302 > DRB1*0401 > DRB1*0404 and the association of DRB1*0401 has a significant effect in DQ8 positive IDDM patients. We conclude that the DR4 association with IDDM is secondary to DQ by linkage disequilibrium, which support the role of HLA-DQ as a primary genetic risk factor for IDDM.
authors.affiliation: Karolinska Institute, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
authors.forename: C B
authors.initials: CB
authors.lastname: Sanjeevi
authors.forename: P
authors.initials: P
authors.lastname: Höök
authors.forename: M
authors.initials: M
authors.lastname: Landin-Olsson
authors.forename: I
authors.initials: I
authors.lastname: Kockum
authors.forename: G
authors.initials: G
authors.lastname: Dahlquist
authors.forename: T P
authors.initials: TP
authors.lastname: Lybrand
authors.forename: A
authors.initials: A
authors.lastname: Lernmark
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016133:Polymerase Chain Reaction; D013548:Sweden
chemical_list: D006683:HLA-DQ Antigens; D015804:HLA-DR4 Antigen