title: PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis.
abstract: The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility.
authors.affiliation: Celera Diagnostics, Alameda, CA 94502, USA.
authors.forename: Victoria E H
authors.initials: VE
authors.lastname: Carlton
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Hu
authors.forename: Anand P
authors.initials: AP
authors.lastname: Chokkalingam
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schrodi
authors.forename: Rhonda
authors.initials: R
authors.lastname: Brandon
authors.forename: Heather C
authors.initials: HC
authors.lastname: Alexander
authors.forename: Monica
authors.initials: M
authors.lastname: Chang
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Catanese
authors.forename: Diane U
authors.initials: DU
authors.lastname: Leong
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Ellen
authors.initials: E
authors.lastname: Beasley
authors.forename: Glenys
authors.initials: G
authors.lastname: Thomson
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Ann B
authors.initials: AB
authors.lastname: Begovich
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012307:Risk Factors
chemical_list: D004247:DNA; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases