PTPN22 R620W Functional Variant in Type 1 Diabetes and Autoimmunity Related Traits
Claude Chelala 1 2 ,
Sabine Duchatelet 1 2 ,
Marie-Line Joffret 1 2 ,
Regine Bergholdt 3 ,
Danièle Dubois-Laforgue 4 5 6 ,
Pegah Ghandil 1 2 ,
Flemming Pociot 3 ,
Sophie Caillat-Zucman 4 5 6 ,
José Timsit 4 5 6 and
Cécile Julier 1 2
1 Institut Pasteur, Genetics of Infectious and Autoimmune Diseases, Paris, France
2 INSERM U730, Paris, France
3 Steno Diabetes Centre, DK-2820 Gentofte, Denmark
4 Department of Diabetology, Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris, France
5 INSERM U561, Paris, France
6 University Paris 5, Paris, France
Address correspondence and reprint requests to C. Julier, Genetics of Infectious and Autoimmune Diseases, INSERM U730, Institut
Pasteur, 28 rue du Docteur Roux, 75724 Paris 15, France. E-mail: cjulier{at}pasteur.fr
Abstract
The PTPN22 gene, encoding the lymphoid-specific protein tyrosine phosphatase, a negative regulator in the T-cell activation and development,
has been associated with the susceptibility to several autoimmune diseases, including type 1 diabetes. Based on combined case-control
and family-based association studies, we replicated the finding of an association of the PTPN22 C1858T (R620W) functional variant with type 1 diabetes, which was independent from the susceptibility status at the insulin
gene and at HLA-DR (DR3/4 compared with others). The risk contributed by the 1858T allele was increased in patients with a
family history of other autoimmune diseases, further supporting a general role for this variant on autoimmunity. In addition,
we found evidence for an association of 1858T allele with the presence of GAD autoantibodies (GADA), which was restricted
to patients with long disease duration (>10 years, P < 0.001). This may help define a subgroup of patients with long-term persistence of GADA. The risk conferred by 1858T allele
on GAD positivity was additive, and our meta-analysis also supported an additive rather than dominant effect of this variant
on type 1 diabetes, similar to previous reports on rheumatoid arthritis and systemic lupus erythematosus.
GADA, GAD autoantibodies
IA2, insuliminoma-associated protein 2
LYP, lymphoid-specific phosphate
SNP, single nucleotide polymorphism
TDT, transmission disequilibrium test
Footnotes
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-0942 .
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 November 6, 2006.
Received July 9, 2006.
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PTPN22 R620W Functional Variant in Type 1 Diabetes and Autoimmunity Related Traits

10.2337/db06-0942