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BIBTEX RIS

Increased representation of the PTPN22 mutation in patients with immune thrombocytopenia

2010; Elsevier BV; Volume: 8; Issue: 9 Linguagem: Inglês

10.1111/j.1538-7836.2010.03954.x

ISSN

1538-7933

Autores

Karl J. D’Silva, M ZAMORA, John A. Gerlach, Kenneth A. Schwartz,

Tópico(s)

Platelet Disorders and Treatments

Resumo

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by antibody‐mediated platelet destruction. Why patients produce an antibody against their own platelets is poorly understood. Twin and family studies suggest that some patients may have a genetic predisposition towards development of ITP [1Laster A.J. Conley C.L. Kickler T. Dorsch C.A. Bias W. Chronic immune thrombocytopenic purpura in monozygotic twins.N Engl J Med. 1982; 307: 1495-8Crossref PubMed Scopus (18) Google Scholar, 2Bizzaro N. Familial association of autoimmune thrombocytopenia and hyperthyroidism.Am J Hematol. 1992; 39: 294-8Crossref PubMed Scopus (24) Google Scholar]. A protein tyrosine phosphatase (ptpn22) present in lymphocytes is an important negative regulator of signal transduction for the T‐cell receptor–MHC complex and has been associated with autoimmune disorders that produce autoantibodies [3Gregersen P.K. Lee H.‐.S. Batliwalla F. Begovich A.B. PTPN22: setting thresholds for autoimmunity.Semin Immunol. 2006; 18: 214-23Crossref PubMed Scopus (204) Google Scholar, 4Kyogoku C. Langefeld C.D. Ortmann W.A. Lee A. Selby S. Carlton V.E.H. Chang M. Ramos P. Baechler E.C. Batliwalla F. Novitzke J. Williams A.H. Gillett C. Rodine P. Graham R.R. Ardlie K.G. Gaffney P.M. Moser K.L. Petri M. Begovich A.B. Gregersen P.K. Behrens T.W. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.Am J Hum Genet. 2004; 75: 504-7Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 5Bottini N. Musumeci L. Alonso A. Rahmouni S. Konstantina N. Rostamkhani M. MacMurray J. Meloni G.F. Lucarelli P. Pellecchia M. Eisenbarth G.S. Comings D. Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-8Crossref PubMed Scopus (1122) Google Scholar, 6Smyth D. Cooper J.D. Collins J.E. Heward J.M. Franklin J.A. Howson J.M.M. Vella A. Nutland S. Rance H.E. Maier L. Barratt B.J. Guja C. Ionescu‐Tirgoviste C. Savage D.A. Dunger D.B. Widmer B. Strachan D.P. Ring S.M. Walker N. Clayton D.G. 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: 3020-3Crossref PubMed Scopus (414) Google Scholar, 7Begovich A.B. Carlton V.E.H. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. Ardlie K.G. Huang Q. Smith Q.M. Spoerke J.M. Conn M.T. Chang M. Chang S.‐.Y.P. Saiki R.K. Cantanese J.J. Leong D.U. Garcia V.E. McAllister L.B. Jeffery D.A. Lee A.T. 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: 330-7Abstract Full Text Full Text PDF PubMed Scopus (1180) Google Scholar]. As ITP patients produce antibodies against their own platelets, we hypothesize that the frequency of the mutation 1858C>T in the PTPN22 gene observed in ITP patients would be increased like the findings reported for other immune disorders. The investigative protocol was approved by the institutional review board of Michigan State University and all patients signed informed consent for genetic testing. Blood samples for genotyping were obtained from 45 unrelated consecutive patients diagnosed with ITP according to the recent definition of the international working group, and who had a positive quantitative direct antiplatelet antibody of at least 500 molecules IgG per platelet [8Rodeghiero F. Stasi R. Gernsheimer T. Michel M. Provan D. Arnold D.M. Bussel J.B. Cines D.B. Chong B.H. Cooper N. Godeau B. Lechner K. Mazzucconi M.G. McMillan R. Sanz M.A. Imbach P. Blanchette V. Kuhne T. Ruggeri M. George J.N. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenia purpura of adults and children: report form an international working group.Blood. 2009; 113: 2386-93Crossref PubMed Scopus (1788) Google Scholar]. Additional inclusion criteria were: a platelet count below 100 000, a marrow morphology, when obtained, compatible with the diagnosis of ITP, no concomitant autoimmune disorders, no medications known to cause thrombocytopenia, no associated viral disorders and no current diagnosis of malignancy. The frequencies of the PTPN22 mutation observed in a population of 926 normal subjects from New York City, (Table 1) as well as the frequencies reported for the immunological disorders listed in (Table 2), were used for statistical comparisons.Table 1ITP compared with controls for the PTPN22 allele and subject frequenciesSubjectsTotal NPercent positive allele‘P’Percent of individuals positive‘P’ReferenceControls9268.7–16.7–7Begovich A.B. Carlton V.E.H. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. Ardlie K.G. Huang Q. Smith Q.M. Spoerke J.M. Conn M.T. Chang M. Chang S.‐.Y.P. Saiki R.K. Cantanese J.J. Leong D.U. Garcia V.E. McAllister L.B. Jeffery D.A. Lee A.T. 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: 330-7Abstract Full Text Full Text PDF PubMed Scopus (1180) Google ScholarITP4515.50.02270.08_ Open table in a new tab Table 2PTPN22 percent positive in ITP patients compared with other immune disordersSubjectsTotal NSubjects positive for the PTPN‐22 allelePercent positive‘P’‐Value for comparison of ITP with other immunologic disordersReferenceITP451227__RA475125260.957Begovich A.B. Carlton V.E.H. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. Ardlie K.G. Huang Q. Smith Q.M. Spoerke J.M. Conn M.T. Chang M. Chang S.‐.Y.P. Saiki R.K. Cantanese J.J. Leong D.U. Garcia V.E. McAllister L.B. Jeffery D.A. Lee A.T. 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: 330-7Abstract Full Text Full Text PDF PubMed Scopus (1180) Google ScholarRA840262310.527Begovich A.B. Carlton V.E.H. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. Ardlie K.G. Huang Q. Smith Q.M. Spoerke J.M. Conn M.T. Chang M. Chang S.‐.Y.P. Saiki R.K. Cantanese J.J. Leong D.U. Garcia V.E. McAllister L.B. Jeffery D.A. Lee A.T. 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: 330-7Abstract Full Text Full Text PDF PubMed Scopus (1180) Google ScholarRA1413328230.599Lee A. Li N. Liew A. Bombardier C. Weisman M. Massarotti E.M. Kent J. Wolfe F. Bergovich A. The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose‐dependent manner but not with HLA‐SE status.Genes Immun. 2005; 6: 129-33Crossref PubMed Scopus (168) Google ScholarRA82616324.50.2613Orozco G. Sanchez E. Gonzalez‐Gay M.A. Lopez‐Novot M.A. Torres B. Caliz R. Ortego‐Centeno N. Jimenez‐Alonso J. Pascual‐Salcedo D. Balsa A. De Pablo R. Nunez‐Roldan A. Gonzales‐Escribano M.F. Martin J. Association of a functional single‐nucleotide polymorphism of PTPN, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosis.Arthritis Rheum. 2005; 52: 219-24Crossref PubMed Scopus (0) Google ScholarRA886299320.3514Hinks A. Barton A. John S. Bruce I. Hawkins C. Griffiths C.E.M. Donn R. Thomson W. Silman A. Worthington J. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population.Arthritis Rheum. 2005; 52: 1694-9Crossref PubMed Scopus (254) Google ScholarRA1514227.80.885Bottini N. Musumeci L. Alonso A. Rahmouni S. Konstantina N. Rostamkhani M. MacMurray J. Meloni G.F. Lucarelli P. Pellecchia M. Eisenbarth G.S. Comings D. Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-8Crossref PubMed Scopus (1122) Google ScholarTID294101340.315Bottini N. Musumeci L. Alonso A. Rahmouni S. Konstantina N. Rostamkhani M. MacMurray J. Meloni G.F. Lucarelli P. Pellecchia M. Eisenbarth G.S. Comings D. Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-8Crossref PubMed Scopus (1122) Google ScholarTID1573496310.496Smyth D. Cooper J.D. Collins J.E. Heward J.M. Franklin J.A. Howson J.M.M. Vella A. Nutland S. Rance H.E. Maier L. Barratt B.J. Guja C. Ionescu‐Tirgoviste C. Savage D.A. Dunger D.B. Widmer B. Strachan D.P. Ring S.M. Walker N. Clayton D.G. 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: 3020-3Crossref PubMed Scopus (414) Google ScholarTID334108320.4415Zhernakova A. Eerligh P. Wijmenga C. Barrera P. Roep B.O. Koeleman B. Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population.Genes Immun. 2005; 6: 459-61Crossref PubMed Scopus (104) Google ScholarTID396106260.3916Zheng W. She J.‐.X. Genetic association between a lymphoid tyrosine phophatase (PTPN22) and Type 1 diabetes.Diabetes. 2005; 54: 906-8Crossref PubMed Scopus (115) Google ScholarSLE705157220.474Kyogoku C. Langefeld C.D. Ortmann W.A. Lee A. Selby S. Carlton V.E.H. Chang M. Ramos P. Baechler E.C. Batliwalla F. Novitzke J. Williams A.H. Gillett C. Rodine P. Graham R.R. Ardlie K.G. Gaffney P.M. Moser K.L. Petri M. Begovich A.B. Gregersen P.K. Behrens T.W. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.Am J Hum Genet. 2004; 75: 504-7Abstract Full Text Full Text PDF PubMed Scopus (553) Google ScholarSLE3386418.90.2213Orozco G. Sanchez E. Gonzalez‐Gay M.A. Lopez‐Novot M.A. Torres B. Caliz R. Ortego‐Centeno N. Jimenez‐Alonso J. Pascual‐Salcedo D. Balsa A. De Pablo R. Nunez‐Roldan A. Gonzales‐Escribano M.F. Martin J. Association of a functional single‐nucleotide polymorphism of PTPN, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosis.Arthritis Rheum. 2005; 52: 219-24Crossref PubMed Scopus (0) Google ScholarSLE57117029.70.6617Reddy L.P.M. Johansson M. Sturfelt G. Jonsen A. Gunnarsson I. Svenungsson E. Rantapaa‐Dahlqvist S. Alarcon‐Riquelme M. The R620W C/T polymorphism of the gene PTPN22 is associated with SLE independently of the association of PDCD1.Genes Immun. 2005; 6: 658-62Crossref PubMed Scopus (62) Google ScholarGD90524026.61.06Smyth D. Cooper J.D. Collins J.E. Heward J.M. Franklin J.A. Howson J.M.M. Vella A. Nutland S. Rance H.E. Maier L. Barratt B.J. Guja C. Ionescu‐Tirgoviste C. Savage D.A. Dunger D.B. Widmer B. Strachan D.P. Ring S.M. Walker N. Clayton D.G. 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: 3020-3Crossref PubMed Scopus (414) Google ScholarGD29010134.80.2818Skorka A. Bednarczuk T. Bar‐Andziak E. Nauman J. Ploski R. Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves’s disease in a Polish population: association and gene dose‐dependent correlatation with the age of onset.Clin Endocrinol. 2005; 62: 679-82Crossref PubMed Scopus (115) Google ScholarGD54914526.50.9719Velaga M. Wilson V. Jennings C. Owens C. Herington S. Donaldson P. Ball S. James R. Quinton R. Perros P. Pearce S. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves Disease.J Clin Endocrinol Metab. 2004; 89: 5862-5Crossref PubMed Scopus (401) Google Scholar Open table in a new tab Genotyping of PTPN22 1858C/T SNP was performed by PCR‐restriction fragment length polymorphism (RFLP) [9Lee A. Li N. Liew A. Bombardier C. Weisman M. Massarotti E.M. Kent J. Wolfe F. Bergovich A. The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose‐dependent manner but not with HLA‐SE status.Genes Immun. 2005; 6: 129-33Crossref PubMed Scopus (168) Google Scholar]. A radiometric technique was used for quantitation of autologous platelet surface IgG [10Schwartz K.A. Gauger J.A. Davis J.M. Precise quantitation of PAIgG: a new radiometric microtechnique.Am J Hematol. 1990; 33: 167-76Crossref PubMed Scopus (4) Google Scholar]. Demographic data describing the patients’ age and race or ethnic background were obtained from the patients. The allele and genotype frequencies among patients with ITP, historical controls and the other immune disorders referenced in Table 1, Table 2 were compared using the χ2‐test. A ‘P’‐value < 0.05 was considered statistically significant. Of the 45 ITP patients studied, 26 (58%) were male and 19 (42%) were female. Median age was 43 years (range, 29–89). Race or ethnic background, as reported by the patients, was 39 Caucasian and 6 Hispanic. Twelve ITP patients (27%) were positive for the single nucleotide polymorphism (SNP) mutation in the gene (PTPN22 1858C>T). Ten patients were heterozygous for the mutation and two were homozygous. The allele frequency of the PTPN 1858 C>T mutation in the ITP patients was 15.5% which is different from the allele frequency of 8.7% reported in 926 adult historical controls (Table 1). (P= 0.026) [7Begovich A.B. Carlton V.E.H. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. Ardlie K.G. Huang Q. Smith Q.M. Spoerke J.M. Conn M.T. Chang M. Chang S.‐.Y.P. Saiki R.K. Cantanese J.J. Leong D.U. Garcia V.E. McAllister L.B. Jeffery D.A. Lee A.T. 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: 330-7Abstract Full Text Full Text PDF PubMed Scopus (1180) Google Scholar]. Comparison of the 27% of the ITP patients who were positive for the PTPN22 1858C>T mutation with the 16.7% positive in the control group yielded a ‘P’‐value of 0.08. The percentage of ITP patients with the PTPN22 1858C>T mutation, 27%, was statistically similar to the citations for genotypic frequencies reported for rheumatoid arthritis, systemic lupus erythematosis, type 1 diabetes and Graves Disease (Table 2) [4Kyogoku C. Langefeld C.D. Ortmann W.A. Lee A. Selby S. Carlton V.E.H. Chang M. Ramos P. Baechler E.C. Batliwalla F. Novitzke J. Williams A.H. Gillett C. Rodine P. Graham R.R. Ardlie K.G. Gaffney P.M. Moser K.L. Petri M. Begovich A.B. Gregersen P.K. Behrens T.W. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.Am J Hum Genet. 2004; 75: 504-7Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar, 5Bottini N. Musumeci L. Alonso A. Rahmouni S. Konstantina N. Rostamkhani M. MacMurray J. Meloni G.F. Lucarelli P. Pellecchia M. Eisenbarth G.S. Comings D. Mustelin T. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.Nat Genet. 2004; 36: 337-8Crossref PubMed Scopus (1122) Google Scholar, 6Smyth D. Cooper J.D. Collins J.E. Heward J.M. Franklin J.A. Howson J.M.M. Vella A. Nutland S. Rance H.E. Maier L. Barratt B.J. Guja C. Ionescu‐Tirgoviste C. Savage D.A. Dunger D.B. Widmer B. Strachan D.P. Ring S.M. Walker N. Clayton D.G. 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: 3020-3Crossref PubMed Scopus (414) Google Scholar, 7Begovich A.B. Carlton V.E.H. Honigberg L.A. Schrodi S.J. Chokkalingam A.P. Alexander H.C. Ardlie K.G. Huang Q. Smith Q.M. Spoerke J.M. Conn M.T. Chang M. Chang S.‐.Y.P. Saiki R.K. Cantanese J.J. Leong D.U. Garcia V.E. McAllister L.B. Jeffery D.A. Lee A.T. 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: 330-7Abstract Full Text Full Text PDF PubMed Scopus (1180) Google Scholar]. The data suggest that at least some ITP patients may have a hereditary predisposition towards developing antibody‐associated thrombocytopenia. PTPN22 is an intracellular tyrosine phosphatase acting immediately downstream from the T‐cell receptor. One working hypothesis is that the PTPN‐22 polymorphism is a gain of function gene that suppresses T‐cell signaling during thymic development allowing autoreactive T cells that normally would be purged to survive [11Vang T. Miletic A.V. Bottini N. Mustelin T. Protein tyrosine phosphatase PTPN22 in human autoimmunity.Autoimmunity. 2007; 40: 453-61Crossref PubMed Scopus (139) Google Scholar]. T‐cell abnormalities are reported in ITP, but the relationship of these changes in T‐cells to the increased representation of the PTPN‐22 polymorphism in ITP patients remains to be investigated [12Semple J.W. Infections, antigen‐prestenting cells, T cells, and immune tolerance: their role in the pathogenesis of immune thrombocytopenia.Hematol Oncol Clin North Am. 2009; 23: 1177-92Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. The reported data are limited by the relatively small number of ITP patients studied, 45, and should be interpreted as a hypothesis generating study. In summary, the PTPN22 1858 C>T allele is present in an increased percentage of ITP patients which is in accord with other autoimmune diseases that are associated with humoral autoantibodies and the PTPN22 polymorphism. K. D’Silva collected, analyzed, interpreted the data and contributed to the manuscript. M. Zamora performed the research, analyzed the data and edited the manuscript. J. Gerlach designed the research, interpreted the data and edited the manuscript. K.A. Schwartz designed the research, collected and analyzed the data, performed statistical analysis and wrote the manuscript. The study was internally funded through the combined efforts of K.A. Schwartz and J. Gerlach’s laboratories. The authors state that they have no conflict of interest.

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