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PTPN22 R620W Functional Variant in Type 1 Diabetes and Autoimmunity Related Traits

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

Abbreviations: GADA, GAD autoantibodies; IA2, insuliminoma-associated protein 2; LYP, lymphoid-specific phosphate; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium test

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.

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