HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0947v1 57/4/1078    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Orilieri, E. Articles by Dianzani, U. Search for Related Content PubMed PubMed Citation Articles by Orilieri, E. Articles by Dianzani, U. Social Bookmarking                What's this?

Variations of the Perforin Gene in Patients With Type 1 Diabetes

¹ Interdisciplinary Research Center of Autoimmune Diseases and Department of Medical Sciences, A. Avogadro University of Eastern Piedmont, Novara, Italy
² Pediatric Haematology-Oncology, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
³ Immunohaematology and Transfusion Center, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
⁴ Department of Pediatric Sciences University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
⁵ Department of Pediatric Sciences, Gaslini Institute-IRCCS, University of Genoa, Genoa, Italy
⁶ Department of Pediatrics, University of Turin, Turin, Italy
⁷ Department of Internal Medicine, University of Turin, Turin, Italy

Address correspondence and reprint requests to Umberto Dianzani, IRCAD-Department of Medical Sciences, Via Solaroli, 17, I-28100, Novara, Italy. E-mail: umberto.dianzani{at}med.unipmn.it

Abbreviations: ALPS, autoimmune lymphoproliferative syndrome; HLH, hemophagocytic lymphohistiocytosis; NK, natural killer; PBMC, peripheral blood mononuclear cells

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 diabetic patients and 816 control subjects and a second population of 365 patients and 964 control subjects. Moreover, we sequenced the coding sequence and intron-exons boundaries in 200 patients and 300 control subjects.

RESULTS—In both cohorts, allelic frequency of N252S was significantly higher in patients than in control subjects (combined cohorts: 1.5 vs. 0.4%; odds ratio 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 control subjects. Typing for HLA-DQA1 and DQB1 alleles showed that type 1 diabetes–predisposing DQ/DQβ heterodimers were less frequent in patients carrying N252S or P477A than in those carrying wild-type PRF1. We previously found that natural killer (NK) activity is not decreased in most N252S heterozygotes, but we 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 susceptibility factors for type 1 diabetes development.

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