title: A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting approximately 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 x 10(-4); replication-study allelic P=5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in approximately 17% of white individuals from the general population and in approximately 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.
authors.affiliation: Celera Diagnostics, Alameda, CA 94502, USA. Ann.Begovich@celeradiagnostics.com
authors.forename: Ann B
authors.initials: AB
authors.lastname: Begovich
authors.forename: Victoria E H
authors.initials: VE
authors.lastname: Carlton
authors.forename: Lee A
authors.initials: LA
authors.lastname: Honigberg
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schrodi
authors.forename: Anand P
authors.initials: AP
authors.lastname: Chokkalingam
authors.forename: Heather C
authors.initials: HC
authors.lastname: Alexander
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: Qiqing
authors.initials: Q
authors.lastname: Huang
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Smith
authors.forename: Jill M
authors.initials: JM
authors.lastname: Spoerke
authors.forename: Marion T
authors.initials: MT
authors.lastname: Conn
authors.forename: Monica
authors.initials: M
authors.lastname: Chang
authors.forename: Sheng-Yung P
authors.initials: SY
authors.lastname: Chang
authors.forename: Randall K
authors.initials: RK
authors.lastname: Saiki
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Catanese
authors.forename: Diane U
authors.initials: DU
authors.lastname: Leong
authors.forename: Veronica E
authors.initials: VE
authors.lastname: Garcia
authors.forename: Linda B
authors.initials: LB
authors.lastname: McAllister
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Jeffery
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Franak
authors.initials: F
authors.lastname: Batliwalla
authors.forename: Elaine
authors.initials: E
authors.lastname: Remmers
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: John J
authors.initials: JJ
authors.lastname: Sninsky
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D005787:Gene Frequency; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009928:Organ Specificity / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012333:RNA, Messenger / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases