Diabetes
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Appendix
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Motzo, C.
Right arrow Articles by Cucca, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Motzo, C.
Right arrow Articles by Cucca, F.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Diabetes 53:3286-3291, 2004
© 2004 by the American Diabetes Association, Inc.

Heterogeneity in the Magnitude of the Insulin Gene Effect on HLA Risk in Type 1 Diabetes

Costantino Motzo1, Daniela Contu1, Heather J. Cordell2, Rosanna Lampis1, Mauro Congia1, Maria Giovanna Marrosu3, John A. Todd2, Marcella Devoto4, and Francesco Cucca1,5

1 Dipartimento di Scienze Biomediche e Biotecnologie, Universita’ di Cagliari, Sardinia, Italy
2 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K
3 Centro Sclerosi Multipla, Dipartimento di Neuroscienze, Universita’ di Cagliari, Sardinia, Italy
4 Department of Research, Nemours Children’s Clinic, Wilmington, DE, and the Dipartimento di Oncologia, Biologia, e Genetica, Universita’ di Genova, Genova, Italy
5 Centro di Genetica Clinica, Dipartimento di Scienze Biomediche, Universita’ di Sassari, Sassari, Italy

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.

Address correspondence and reprint requests to Francesco Cucca, Universita’ di Cagliari, Dipartimento di Scienze Biomediche e Biotecnologie, Via Jenner, Cagliari, 09124 Italy. E-mail: fcucca{at}mcweb.unica.it


Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.