Abstract
The 620W allele of PTPN22 has been associated with susceptibility to several different forms of chronic inflammatory disease, including Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroiditis (AIT). We set out to explore its possible role in two other inflammatory diseases: multiple sclerosis (MS) and Crohn's disease (CD). In our cohort of 496 MS trios from the United Kingdom, we observed reduced transmission of the PTPN22 620W allele. The CD sample consisted of 169 trios as well as 249 cases of CD with their 207 matched control subjects collected in the province of Québec, Canada; there was also no evidence of association between the PTPN22 620W allele and susceptibility for CD. Pooled analyses combining our data with published data assessed a total of 1496 cases of MS and 1019 cases of CD but demonstrated no evidence of association with either disease. Given the modest odds ratios of known risk alleles for inflammatory diseases, these analyses do not exclude a role for the PTPN22 allele in susceptibility to CD or MS, but they do suggest that such a putative role would probably be more modest than that reported so far in T1D, RA, SLE, and AIT.
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References
Bottini N, Musumeci L, Alonso A et al: A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004; 36: 337–338.
Begovich AB, Carlton VE, Honigberg LA et al: A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004; 75: 330–337.
Begovich AB, Caillier SJ, Alexander HC et al: The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. Am J Hum Genet 2005; 76: 184–187.
Kyogoku C, Langefeld CD, Ortmann WA et al: Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004; 75: 504–507.
Hasegawa K, Martin F, Huang G et al: PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 2004; 303: 685–689.
Wen Z, Fiocchi C : Inflammatory bowel disease: autoimmune or immune-mediated pathogenesis? Clin Dev Immunol 2004; 11: 195–204.
Hafler DA, Slavik JM, Anderson DE et al: Multiple sclerosis. Immunol Rev 2005; 204: 208–231.
Smyth D, Cooper JD, Collins JE et al: Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53: 3020–3023.
Criswell LA, Pfeiffer KA, Lum RF et al: Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 2005; 76: 561–571.
Cho JH, Nicolae DL, Gold LH et al: Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci USA 1998; 95: 7502–7507.
Hensiek AE, Roxburgh R, Smilie B et al: Updated results of the United Kingdom linkage-based genome screen in multiple sclerosis. J Neuroimmunol 2003; 143: 25–30.
Dyment DA, Sadovnick AD, Willer CJ et al: An extended genome scan in 442 Canadian multiple sclerosis-affected sibships: a report from the Canadian Collaborative Study Group. Hum Mol Genet 2004; 13: 1005–1015.
Kenealy SJ, Babron MC, Bradford Y et al: A second-generation genomic screen for multiple sclerosis. Am J Hum Genet 2004; 75: 1070–1078.
van Heel DA, Fisher SA, Kirby A et al: Genome scan meta-analysis group of the IBD international genetics consortium. Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet 2004; 13: 763–770.
GAMES; Transatlantic Multiple Sclerosis Genetics Cooperative: A meta-analysis of whole genome linkage screens in multiple sclerosis. J Neuroimmunol 2003; 143: 39–46.
Sawcer S, Ban M, Maranian M et al: A high-density screen for linkage in multiple sclerosis. Am J Hum Genet 2005; 77: 454–467.
Matesanz F, Rueda B, Orozco G et al: Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis. J Neurol 2005; 252: 994–995.
Hinks A, Barton A, John S et al: Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum 2005; 52: 1694–1699.
van Oene M, Wintle RF, Liu X et al: Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations. Arthritis Rheum 2005; 52: 1993–1998.
Wagenleiter SE, Klein W, Griga T et al: A case-control study of tyrosine phosphatase (PTPN22) confirms the lack of association with Crohn's disease. Int J Immunogenet 2005; 32: 323–324.
Poser CM, Paty DW, Scheinberg L et al: New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.
Lennard-Jones JE : Classification of inflammatory bowel disease. Scand J Gastroenterol 1989; 170: 2–6.
Vermeire S, Wild G, Kocher K et al: CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. Am J Hum Genet 2002; 71: 74–83.
Spielman RS, Ewens WJ : The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 199; 59: 983–989.
Daly MJ, Kruglyak L, Pratt S et al: GENEHUNTER 2.0-a complete linkage analysis system. Am J Hum Genet 1998; 63: S286.
Morris JA, Gardner MJ : Calculating confidence intervals for relative risks (odds ratios) and standardised ratios and rates. Br Med J (Clin Res Ed) 1988; 296: 1313–1316.
McDonald WI, Compston A, Edan G et al: Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.
Purcell S, Cherny SS, Sham PC : Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.
Acknowledgements
We thank Drs AB Begovich and J Oksenberg for sharing their genotyping data. PLD is the William C Fowler scholar in Multiple Sclerosis and is supported by an NINDS K08 grant as well as the Clinical Investigator Training Program: Harvard-MIT Health Sciences and Technology Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. JDR is supported by grants from the NIDDK and the CCFA. The authors have no conflicts of interest to report.
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De Jager, P., Sawcer, S., Waliszewska, A. et al. Evaluating the role of the 620W allele of protein tyrosine phosphatase PTPN22 in Crohn's disease and multiple sclerosis. Eur J Hum Genet 14, 317–321 (2006). https://doi.org/10.1038/sj.ejhg.5201548
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DOI: https://doi.org/10.1038/sj.ejhg.5201548
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