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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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

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Protein Tyrosine Phosphatases
Single Nucleotide Polymorphism
Rheumatoid Arthritis
Genes
Alleles
Autoimmune Diseases
Type 1 Diabetes Mellitus
Phosphoric Monoester Hydrolases
Proline
Population
Case-Control Studies
Immune System
T-Lymphocytes
Proteins

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., ... 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

A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. / Begovich, Ann B.; Carlton, Victoria E H; Honigberg, Lee A.; Schrodi, Steven J.; Chokkalingam, Anand P.; Alexander, Heather C.; Ardlie, Kristin G.; Huang, Qiqing; Smith, Ashley M.; Spoerke, Jill M.; Conn, Marion T.; Chang, Monica; Chang, Sheng Yung P; Saiki, Randall K.; Catanese, Joseph J.; Leong, Diane U.; Garcia, Veronica E.; McAllister, Linda B.; Jeffery, Douglas A.; Lee, Annette T.; Batliwalla, Franak; Remmers, Elaine; Criswell, Lindsey A.; Seldin, Michael F; Kastner, Daniel L.; Amos, Christopher I.; Sninsky, John J.; Gregersen, Peter K.

In: American Journal of Human Genetics, Vol. 75, No. 2, 08.2004, p. 330-337.

Research output: Contribution to journalArticle

Begovich, AB, Carlton, VEH, Honigberg, LA, Schrodi, SJ, Chokkalingam, AP, Alexander, HC, Ardlie, KG, Huang, Q, Smith, AM, Spoerke, JM, Conn, MT, Chang, M, Chang, SYP, Saiki, RK, Catanese, JJ, Leong, DU, Garcia, VE, McAllister, LB, Jeffery, DA, Lee, AT, Batliwalla, F, Remmers, E, Criswell, LA, Seldin, MF, Kastner, DL, Amos, CI, Sninsky, JJ & Gregersen, PK 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, vol. 75, no. 2, pp. 330-337. https://doi.org/10.1086/422827
Begovich, Ann B. ; Carlton, Victoria E H ; Honigberg, Lee A. ; Schrodi, Steven J. ; Chokkalingam, Anand P. ; Alexander, Heather C. ; Ardlie, Kristin G. ; Huang, Qiqing ; Smith, Ashley M. ; Spoerke, Jill M. ; Conn, Marion T. ; Chang, Monica ; Chang, Sheng Yung P ; Saiki, Randall K. ; Catanese, Joseph J. ; Leong, Diane U. ; Garcia, Veronica E. ; McAllister, Linda B. ; Jeffery, Douglas A. ; Lee, Annette T. ; Batliwalla, Franak ; Remmers, Elaine ; Criswell, Lindsey A. ; Seldin, Michael F ; Kastner, Daniel L. ; Amos, Christopher I. ; Sninsky, John J. ; Gregersen, Peter K. / A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. In: American Journal of Human Genetics. 2004 ; Vol. 75, No. 2. pp. 330-337.
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AU - Begovich, Ann B.

AU - Carlton, Victoria E H

AU - Honigberg, Lee A.

AU - Schrodi, Steven J.

AU - Chokkalingam, Anand P.

AU - Alexander, Heather C.

AU - Ardlie, Kristin G.

AU - Huang, Qiqing

AU - Smith, Ashley M.

AU - Spoerke, Jill M.

AU - Conn, Marion T.

AU - Chang, Monica

AU - Chang, Sheng Yung P

AU - Saiki, Randall K.

AU - Catanese, Joseph J.

AU - Leong, Diane U.

AU - Garcia, Veronica E.

AU - McAllister, Linda B.

AU - Jeffery, Douglas A.

AU - Lee, Annette T.

AU - Batliwalla, Franak

AU - Remmers, Elaine

AU - Criswell, Lindsey A.

AU - Seldin, Michael F

AU - Kastner, Daniel L.

AU - Amos, Christopher I.

AU - Sninsky, John J.

AU - Gregersen, Peter K.

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