title: Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes.
abstract: There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.
authors.affiliation: Dipartimento di Scienze Biomediche e Biotecnologie, Universita' di Cagliari, Sardinia, Italy.
authors.forename: Costantino
authors.initials: C
authors.lastname: Motzo
authors.forename: Daniela
authors.initials: D
authors.lastname: Contu
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Rosanna
authors.initials: R
authors.lastname: Lampis
authors.forename: Mauro
authors.initials: M
authors.lastname: Congia
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D005190:Family; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D012016:Reference Values; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains