Variations of the perforin gene in patients with type 1 diabetes

Elisabetta Orilieri, Giuseppe Cappellano, Rita Clementi, Angela Cometa, Massimo Ferretti, Elisa Cerutti, Francesco Cadario, Miryam Martinetti, Daniela Larizza, Valeria Calcaterra, Giuseppe D'Annunzio, Renata Lorini, Franco Cerutti, Graziella Bruno, Annalisa Chiocchetti, Umberto Dianzani

Research output: Contribution to journalArticle

Abstract

OBJECTIVE-Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophago-cytic 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 DQα/DQP 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.

Original languageEnglish
Pages (from-to)1078-1083
Number of pages6
JournalDiabetes
Volume57
Issue number4
DOIs
Publication statusPublished - Apr 2008

Fingerprint

Perforin
Type 1 Diabetes Mellitus
Genes
Heterozygote
Autoimmune Lymphoproliferative Syndrome
Mutation
Introns
Population
Exons
Lymphoma
Research Design
Alleles
Odds Ratio
Amino Acids

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Orilieri, E., Cappellano, G., Clementi, R., Cometa, A., Ferretti, M., Cerutti, E., ... Dianzani, U. (2008). Variations of the perforin gene in patients with type 1 diabetes. Diabetes, 57(4), 1078-1083. https://doi.org/10.2337/db07-0947

Variations of the perforin gene in patients with type 1 diabetes. / Orilieri, Elisabetta; Cappellano, Giuseppe; Clementi, Rita; Cometa, Angela; Ferretti, Massimo; Cerutti, Elisa; Cadario, Francesco; Martinetti, Miryam; Larizza, Daniela; Calcaterra, Valeria; D'Annunzio, Giuseppe; Lorini, Renata; Cerutti, Franco; Bruno, Graziella; Chiocchetti, Annalisa; Dianzani, Umberto.

In: Diabetes, Vol. 57, No. 4, 04.2008, p. 1078-1083.

Research output: Contribution to journalArticle

Orilieri, E, Cappellano, G, Clementi, R, Cometa, A, Ferretti, M, Cerutti, E, Cadario, F, Martinetti, M, Larizza, D, Calcaterra, V, D'Annunzio, G, Lorini, R, Cerutti, F, Bruno, G, Chiocchetti, A & Dianzani, U 2008, 'Variations of the perforin gene in patients with type 1 diabetes', Diabetes, vol. 57, no. 4, pp. 1078-1083. https://doi.org/10.2337/db07-0947
Orilieri E, Cappellano G, Clementi R, Cometa A, Ferretti M, Cerutti E et al. Variations of the perforin gene in patients with type 1 diabetes. Diabetes. 2008 Apr;57(4):1078-1083. https://doi.org/10.2337/db07-0947
Orilieri, Elisabetta ; Cappellano, Giuseppe ; Clementi, Rita ; Cometa, Angela ; Ferretti, Massimo ; Cerutti, Elisa ; Cadario, Francesco ; Martinetti, Miryam ; Larizza, Daniela ; Calcaterra, Valeria ; D'Annunzio, Giuseppe ; Lorini, Renata ; Cerutti, Franco ; Bruno, Graziella ; Chiocchetti, Annalisa ; Dianzani, Umberto. / Variations of the perforin gene in patients with type 1 diabetes. In: Diabetes. 2008 ; Vol. 57, No. 4. pp. 1078-1083.
@article{f2d6362b1913423cb72f60ab3288bafb,
title = "Variations of the perforin gene in patients with type 1 diabetes",
abstract = "OBJECTIVE-Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophago-cytic 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 DQα/DQP 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.",
author = "Elisabetta Orilieri and Giuseppe Cappellano and Rita Clementi and Angela Cometa and Massimo Ferretti and Elisa Cerutti and Francesco Cadario and Miryam Martinetti and Daniela Larizza and Valeria Calcaterra and Giuseppe D'Annunzio and Renata Lorini and Franco Cerutti and Graziella Bruno and Annalisa Chiocchetti and Umberto Dianzani",
year = "2008",
month = "4",
doi = "10.2337/db07-0947",
language = "English",
volume = "57",
pages = "1078--1083",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "4",

}

TY - JOUR

T1 - Variations of the perforin gene in patients with type 1 diabetes

AU - Orilieri, Elisabetta

AU - Cappellano, Giuseppe

AU - Clementi, Rita

AU - Cometa, Angela

AU - Ferretti, Massimo

AU - Cerutti, Elisa

AU - Cadario, Francesco

AU - Martinetti, Miryam

AU - Larizza, Daniela

AU - Calcaterra, Valeria

AU - D'Annunzio, Giuseppe

AU - Lorini, Renata

AU - Cerutti, Franco

AU - Bruno, Graziella

AU - Chiocchetti, Annalisa

AU - Dianzani, Umberto

PY - 2008/4

Y1 - 2008/4

N2 - OBJECTIVE-Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophago-cytic 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 DQα/DQP 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.

AB - OBJECTIVE-Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophago-cytic 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 DQα/DQP 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.

UR - http://www.scopus.com/inward/record.url?scp=42449112039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42449112039&partnerID=8YFLogxK

U2 - 10.2337/db07-0947

DO - 10.2337/db07-0947

M3 - Article

C2 - 18198357

AN - SCOPUS:42449112039

VL - 57

SP - 1078

EP - 1083

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -