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

Research output: Contribution to journalArticlepeer-review

1105 Scopus citations

Abstract

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
Volume75
Issue number2
DOIs
StatePublished - Aug 2004

ASJC Scopus subject areas

  • Genetics

Fingerprint

Dive into the research topics of 'A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis'. Together they form a unique fingerprint.

Cite this