Further Evidence of a Primary, Causal Association of the PTPN22 620W Variant With Type 1 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 1; pp. 229 - 234
• Main Authors: ZOLEDZIEWSKA, Magdalena, PERRA, Chiara, ORRH, Valeria, MOI, Loredana, FRONGIA, Paola, CONGIA, Mauro, BOTTINI, Nunzio, CUCCA, Francesco
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-01-2008
• Subjects: Adolescent; Adult; Autoimmune diseases; Autoimmune Diseases - genetics; Biological and medical sciences; Child; Child, Preschool; Development and progression; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes. Impaired glucose tolerance; Disease; DNA - blood; DNA - genetics; DNA sequencing; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; European Continental Ancestry Group - genetics; Gene Frequency; Genes; Genetic aspects; Genetic Variation; Genotype; Haplotypes; Humans; Infant; Italy; Linkage Disequilibrium; Medical sciences; Mutation; Nucleotide sequencing; Parents & parenting; Phosphatase; Polymorphism; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics; Reference Values; Research design; Rheumatoid arthritis; Type 1 diabetes; Italy; Endocrinopathy; Variant; Immunopathology; Autoimmune disease; Association; Type 1 diabetes
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db07-0289

Further Evidence of a Primary, Causal Association of the PTPN22 620W Variant With Type 1 Diabetes
Magdalena Zoledziewska 1 2 ,
Chiara Perra 2 † ,
Valeria Orrù 1 3 ,
Loredana Moi 2 ,
Paola Frongia 4 ,
Mauro Congia 2 ,
Nunzio Bottini 3 and
Francesco Cucca 1
1 Dipartimento di Scienze Biomediche, University of Sassari, Sassari, Italy
2 Laboratorio di Immunogenetica, Ospedale Microcitemico, Cagliari, Italy
3 Institute for Genetic Medicine, University of Southern California, Los Angeles, California
4 Divisione Pediatrica, Ospedale Brotzu, Cagliari, Italy
Address correspondence and reprint requests to Francesco Cucca, Cattedra di Genetica Medica, Dipartimento di Scienze Biomediche,
Università di Sassari, Viale S. Pietro, 07100 Sassari, Italy. E-mail: fcucca{at}uniss.it
Abstract
OBJECTIVE— The minor allele of the nonsynonymous single nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene is positively associated with type 1 diabetes and other autoimmune diseases. Genetic and functional data underline its
causal effect, but some studies suggest that this polymorphism does not entirely explain disease association of the PTPN22 region. The aim of this study was to evaluate type 1 diabetes association within this gene in the Sardinian population.
RESEARCH DESIGN AND METHODS— We resequenced the exons and potentially relevant portions of PTPN22 and detected 24 polymorphisms (23 SNPs and 1 deletion insertion polymorphism [DIP]), 8 of which were novel. A representative
set of 14 SNPs and the DIP were sequentially genotyped and assessed for disease association in 794 families, 490 sporadic
patients, and 721 matched control subjects.
RESULTS— The +1858C>T variant, albeit rare in the general Sardinian population (allele frequency 0.014), was positively associated
with type 1 diabetes ( P one tail = 3.7 × 10 −3 ). In contrast, the background haplotype in which this mutation occurred was common (haplotype frequency 0.117) and neutrally
associated with disease. We did not confirm disease associations reported in other populations for non +1858C>T variants (rs2488457,
rs1310182, and rs3811021), although they were present in appreciable frequencies in Sardinia. Additional weak disease associations
with rare variants were detected in the Sardinian families but not confirmed in independent case-control sample sets and are
most likely spurious.
CONCLUSIONS— We provide further evidence that the +1858C>T polymorphism is primarily associated with type 1 diabetes and exclude major
contributions from other purportedly relevant variants within this gene.
AFBAC, affected family–based control
DIP, deletion insertion polymorphism
HLA, human leukocyte antigen
Lyp, lymphoid protein tyrosine phosphatase
MAF, minor allele frequency
SNP, single nucleotide polymorphism
TDT, transmission disequilibrium test
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 12 October 2007. DOI: 10.2337/db07-0289.
M.Z., C.P., and V.O. contributed equally to this work.
†
† C.P. is deceased.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted October 7, 2007.
Received March 1, 2007.
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