A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis

Ann B. Begovich, Victoria E H Carlton, Lee A. Honigberg, Steven J. Schrodi, Anand P. Chokkalingam, Heather C. Alexander, Kristin G. Ardlie, Qiqing Huang, Ashley M. Smith, Jill M. Spoerke, Marion T. Conn, Monica Chang, Sheng Yung P Chang, Randall K. Saiki, Joseph J. Catanese, Diane U. Leong, Veronica E. Garcia, Linda B. McAllister, Douglas A. Jeffery, Annette T. LeeFranak Batliwalla, Elaine Remmers, Lindsey A. Criswell, Michael F Seldin, Daniel L. Kastner, Christopher I. Amos, John J. Sninsky, Peter K. Gregersen

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Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting ∼1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P = 6.6 × 10-4; replication-study allelic P = 5.6 × 10-8), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in ∼17% of white individuals from the general population and in ∼28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease.

Original languageEnglish (US)
Pages (from-to)330-337
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Aug 2004


ASJC Scopus subject areas

  • Genetics

Cite this

Begovich, A. B., Carlton, V. E. H., Honigberg, L. A., Schrodi, S. J., Chokkalingam, A. P., Alexander, H. C., Ardlie, K. G., Huang, Q., Smith, A. M., Spoerke, J. M., Conn, M. T., Chang, M., Chang, S. Y. P., Saiki, R. K., Catanese, J. J., Leong, D. U., Garcia, V. E., McAllister, L. B., Jeffery, D. A., ... Gregersen, P. K. (2004). A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. American Journal of Human Genetics, 75(2), 330-337. https://doi.org/10.1086/422827