title: The HLA-DRB, -DQB polymorphism and anti-insulin antibody response in Slovenian patients with type 1 diabetes.
abstract: A combination of specific HLA class II antigens and the presence of type 1 diabetes (T1D)-related antibodies has a high positive predictive value for T1D but low sensitivity. The aim of the present study was to determine the frequencies of HLA-DRB-DQB deduced haplotypes associated with susceptibility and protection in Slovenian patients with established T1D, to evaluate the relationship between the HLA-DRB1-QBP-DQB1 haplotypes and the presence of insulin autoantibodies (IAA) and glutamic acid decarboxylase antibodies (GADA), and to access the possible impact of polymorphic QBP promoters on this relationship. A cohort of 135 patients with T1D (age 17.5 +/- 7.0 years, duration of T1D 9.14 +/- 6.3 years) was investigated. HLA-DRB1 and DQB1 alleles were typed using the polymerase chain reaction (PCR)-reverse line blot method. QBP promoter region alleles were determined using PCR-sequence-specific oligonucleotide hybridization (SSO) and PCR-sequence-specific primers (SSP). IAA and GADA antibodies were determined by enzyme-linked immunosorbent assay (ELISA). The chi-square test with Yates' correction was used for statistical analysis. Deduced haplotypes DRB1*0301-DQB1*0201 (P = 0.0001, OR = 3.4), DRB1*0401-DQB1*0302 (P = 0.0001, OR = 29.8), and DRB1*0402-DQB1*0302 (P = 0.008, OR = 4.7) were significantly more common, and DRB1*1501-DQB1*0602 (P = 0.0001, OR = 0.03) significantly less common in the investigated cohort than in a Slovenian control group. The highest risk and the strongest protective HLA-DR-DQ haplotypes found in Slovenian patients with T1D did not differ from those found in other Caucasian populations. While the DRB1*0301-QBP2.1-DQB1*0201 haplotype, where QBP2.1 did not help to further distinguish DQB1*0201-possessing haplotypes in IAA-positive and IAA-negative patients, was strongly associated with the presence of IAA, the DRB1*0101-QBP5.12-DQB1*0501 haplotype, although not protective compared to the control population, was associated with an absence of IAA in the investigated cohort. It is suggested that there may be a combined influence of the QBP5.12 promoter and the DQB1*0501 functional molecule on reduced IAA production.
authors.affiliation: University Children's Hospital, Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, Ljubljana, Slovenia. tadej.battelino@mf.uni-lj.si
authors.forename: T
authors.initials: T
authors.lastname: Battelino
authors.forename: N
authors.initials: N
authors.lastname: Ursic-Bratina
authors.forename: V
authors.initials: V
authors.lastname: Dolzan
authors.forename: M
authors.initials: M
authors.lastname: Stopar-Obreza
authors.forename: P
authors.initials: P
authors.lastname: Pozzilli
authors.forename: C
authors.initials: C
authors.lastname: Krzisnik
authors.forename: B
authors.initials: B
authors.lastname: Vidan-Jeras
mesh_terms: D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000276:immunology; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007328:Insulin / Q000276:immunology; D011110:Polymorphism, Genetic; D017524:Slovenia; D044465:White People / Q000235:genetics
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; C553506:HLA-DRB1*04:02 antigen; D007328:Insulin; D005968:Glutamate Decarboxylase