[PDF][PDF] The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis

AB Begovich, SJ Caillier, HC Alexander… - The American Journal of …, 2005 - cell.com
AB Begovich, SJ Caillier, HC Alexander, JM Penko, SL Hauser, LF Barcellos, JR Oksenberg
The American Journal of Human Genetics, 2005cell.com
We recently reported the association of the minor allele of a missense SNP (1858CrT
[dbSNP accession number rs2476601]) in the gene for hematopoietic-specific intracellular
protein tyrosine phosphatase (PTPN22) with susceptibility to both rheumatoid arthritis (RA
[MIM 180300])(Begovich et al. 2004) and systemic lupus erythematosus (SLE [MIM
152700])(Kyogoku et al. 2004). Independently, Bottini et al.(2004) reported that the same
risk allele is also strongly associated with type 1 diabetes mellitus (T1D [MIM 222100]). This …
We recently reported the association of the minor allele of a missense SNP (1858CrT [dbSNP accession number rs2476601]) in the gene for hematopoietic-specific intracellular protein tyrosine phosphatase (PTPN22) with susceptibility to both rheumatoid arthritis (RA [MIM 180300])(Begovich et al. 2004) and systemic lupus erythematosus (SLE [MIM 152700])(Kyogoku et al. 2004). Independently, Bottini et al.(2004) reported that the same risk allele is also strongly associated with type 1 diabetes mellitus (T1D [MIM 222100]). This SNP results in the substitution of a highly conserved arginine with tryptophan (R620W) in the proximal proline-rich SH3-binding domain of PTPN22, which is important for interaction with the c-Src tyrosine kinase, Csk (Cloutier and Veillette 1996; Gregorieff et al. 1998), and for down modulation of T cell receptor signaling via phosphorylation of regulatory tyrosines of another Src family kinase, Lck (Cloutier and Veillette 1999; Gjorloff-Wingren et al. 1999). In vitro experiments show that the W620 variant of PTPN22 binds less efficiently to Csk (Begovich et al. 2004; Bottini et al. 2004), suggesting that T cells expressing this allele may be hyperresponsive. Correspondingly, knockout mice deficient in the murine orthologue of PTPN22, PEP, show selective disregulation of the effector/memory T cell compartment, with enhanced activation of Lck, hyperproliferation, and exaggerated early signaling responses in restimulated T cells (Hasegawa et al. 2004). These mice also spontaneously develop germinal centers and increased serum levels of certain immunoglobulin isotypes; however, they do not display overt signs of autoimmunity. Together, these genetic and functional data suggest that the W620 variant of this phosphatase is a significant genetic risk factor for both organ-specific (T1D) and systemic (RA and SLE) autoimmune syndromes, perhaps because of enhanced activation of memory/effector T cells. These findings support the hypothesis that there are common genetic variants contributing to general immune dysregulation and susceptibility to autoimmunity (Marrack et al. 2001; Wandstrat and Wakeland 2001) and suggest that this SNP should be studied in other autoimmune disorders. Multiple sclerosis (MS [MIM 126200]) is a severe autoimmune disorder of the CNS characterized by chronic inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction (Hauser and Goodin 2001). A large body of research supports a multifactorial etiology for MS, with an underlying complex genetic component likely acting in concert with undefined environmental exposures. HLA-DR, within the MHC on chromosome 6p21, is the only locus that has consistently demonstrated linkage in studies of families with MS (Haines et al. 1996; Sawcer et al. 1996; Barcellos et al. 2002), and both family-based and case-control MS studies have convincingly shown a specific association between the HLA-DR2 (DRB1* 1501, DQB1* 0602) haplotype and disease susceptibility (Fogdell-Hahn et al. 2000; Rubio et al. 2002; Barcellos et al. 2003). HLA has been estimated to account for 17%–62% of the genetic etiology as calculated from sibling relative risk (Haines et al. 1998); hence, much of the genetic effect in MS remains to be explained. To determine whether the R620W SNP in PTPN22 also plays a role in susceptibility to MS, we genotyped two large, well-characterized, family-based data sets of 748 MS-prone families (563 single-case and 185 multicase families) comprising 3,251 individuals, including 1,086 affected individuals and 2,165 unaffected family members. All individuals and their known ancestors were …
cell.com