VARIATIONS OF THE PERFORIN GENE IN PATIENTS WITH TYPE 1 DIABETES
- Elisabetta Orilieri, MS1,
- Giuseppe Cappellano, MS1,
- Rita Clementi, MD2,
- Angela Cometa, PhD2,
- Massimo Ferretti, MS1,
- Elisa Cerutti, MS1,
- Francesco Cadario, MD1,
- Miryam Martinetti, MS3,
- Daniela Larizza, MD4,
- Valeria Calcaterra, MD4,
- Giuseppe D'Annunzio, MD5,
- Renata Lorini, MD5,
- Franco Cerutti, MD6,
- Graziella Bruno, MD7,
- Annalisa Chiocchetti, PhD1 and
- Umberto Dianzani, MD (umberto.dianzani{at}med.unipmn.it)1
- 1Interdisciplinary Research Center of Autoimmune Diseases and Department of Medical Sciences, “A. Avogadro“ University of Eastern Piedmont, Novara, Italy
- 2Pediatric Haematology-Oncology,
- 3Immunohaematology and Transfusion Center, and
- 4Department of Pediatric Sciences University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- 5Department of Pediatric Sciences, Gaslini Institute-IRCCS, University of Genoa, Genoa, Italy
- 6Department of Pediatrics and
- 7Department of Internal Medicine, University of Turin, Turin, Italy
Abstract
Objective: Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene (PRF1) cause familial hemophagocytic lymphohistiocytosis, but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome. The aim of this work was to investigate the role of PRF1 variations in type 1 diabetes.
Research Design and Methods: We typed for the N252S and A91V variations in an initial population of 352 type 1 diabetes patients and 816 controls, and a second population of 365 patients and 964 controls. Moreover, we sequenced the coding sequence and intron-exons boundaries in 200 patients and 300 controls.
Results: In both cohorts, allelic frequency of N252S was significantly higher in patients than in controls (combined cohorts: 1.5 vs 0.4%, OR=6.68, 95%CI=1.83-7.48). Sequencing of the entire coding region detected one novel mutation in one patient causing a P477A amino acid change not detected in 199 patients and 300 controls. Typing for HLA-DQA1 and DQB1 alleles showed that type 1 diabetes predisposing DQα/DQβ heterodimers were less frequent in patients carrying N252S or P477A than in those carrying wild-type PRF1. We previously found that NK activity is not decreased in most N252S heterozygotes, but detected one whose NK activity was normal at the age of 12, but strikingly low in early childhood. Here, we discovered that NK function was low in three heterozygotes in early childhood, one homozygous adult, and in the subject carrying P477A.
Conclusions: These data suggest that N252S and possibly other PRF1 variations are a susceptibility factor for type 1 diabetes development.
Footnotes
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- Received July 10, 2007.
- Accepted January 9, 2008.
- Copyright © American Diabetes Association
