Annals of Hematology

, Volume 89, Supplement 1, pp 95–103 | Cite as

Genetic studies in pediatric ITP: outlook, feasibility, and requirements

  • Anke K. Bergmann
  • Rachael F. Grace
  • Ellis J. Neufeld
Future Research

Abstract

The genomic revolution in medicine has not escaped attention of clinicians and scientists involved in medical management and research studies of immune thrombocytopenic purpura (ITP). In principle, ITP biology and care will benefit greatly from modern methods to understand the patterns of gene expression and genetic markers associated with fundamental parameters of the disease including predictors of remission, risk factors for severity, determinants of response to various therapies, and possibly biological sub-types. However, applying modern genetics to ITP carries severe challenges: (a) Achieving adequate sample sizes is a fundamental problem because ITP is rare (and in pediatric ITP, chronic cases constitute only about one fourth of the total); (b) familial transmission of childhood ITP is so rare that a convincing pedigree requires consideration of other immunologic or hematologic disorders; (iii) ITP is probably biologically heterogeneous, based on clinical observations, immunological studies, and animal models. Here we review the advantages and disadvantages of potential genetic approaches. Sufficient information is available to set reasonable bounds on which genetic analyses of ITP are feasible and how they are most likely to be accomplished. The highest priority is for accurate phenotypes to compare to genetic analyses. Several registries worldwide hold promise for accomplishing this goal.

Keywords

GWAS Immune thrombocytopenic purpura Registries Cohort studies 

References

  1. 1.
    Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, Bussel JB, Cines DB, Chong BH, Cooper N, Godeau B, Lechner K, Mazzucconi MG, McMillan R, Sanz MA, Imbach P, Blanchette V, Kuhne T, Ruggeri M, George JN (2009) Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 113:2386–2393CrossRefPubMedGoogle Scholar
  2. 2.
    George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMillan R, Okerbloom JA, Regan DH, Warrier I (1996) Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 88:3–40PubMedGoogle Scholar
  3. 3.
    De Mattia D, Del Principe D, Del Vecchio GC, Jankovic M, Arrighini A, Giordano P, Menichelli A, Mori P, Zecca M, Pession A (2000) Acute childhood idiopathic thrombocytopenic purpura: AIEOP consensus guidelines for diagnosis and treatment. Associazione Italiana di ematologia e oncologia pediatrica. Haematologica 85:420–424PubMedGoogle Scholar
  4. 4.
    British Committee for Standards in Haematology General Haematology Task Force (2003) Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 120:574–596CrossRefGoogle Scholar
  5. 5.
    Neunert CE, Bright BC, Buchanan GR (2008) Severe chronic refractory immune thrombocytopenic purpura during childhood: a survey of physician management. Pediatr Blood Cancer 51:513–516CrossRefPubMedGoogle Scholar
  6. 6.
    Cines DB, Liebman H, Stasi R (2009) Pathobiology of secondary immune thrombocytopenia. Semin Hematol 46:S2–S14CrossRefPubMedGoogle Scholar
  7. 7.
    Cines DB, McMillan R (2007) Pathogenesis of chronic immune thrombocytopenic purpura. Curr Opin Hematol 14:511–514CrossRefPubMedGoogle Scholar
  8. 8.
    Cooper N, Bussel J (2006) The pathogenesis of immune thrombocytopaenic purpura. Br J Haematol 133:364–374CrossRefPubMedGoogle Scholar
  9. 9.
    Keen-Kim D, Mathews CA, Reus VI, Lowe TL, Herrera LD, Budman CL, Gross-Tsur V, Pulver AE, Bruun RD, Erenberg G, Naarden A, Sabatti C, Freimer NB (2006) Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses. Hum Mol Genet 15:3324–3328CrossRefPubMedGoogle Scholar
  10. 10.
    Mitrovic Z, Aurer I, Radman I, Ajdukovic R, Sertic J, Labar B (2007) FCgammaRIIIA and FCgammaRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma. Haematologica 92:998–999CrossRefPubMedGoogle Scholar
  11. 11.
    Kim DH, Jung HD, Kim JG, Lee JJ, Yang DH, Park YH, Do YR, Shin HJ, Kim MK, Hyun MS, Sohn SK (2006) FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood 108:2720–2725CrossRefPubMedGoogle Scholar
  12. 12.
    Marsh S, Van Booven DJ (2009) The increasing complexity of mercaptopurine pharmacogenomics. Clin Pharmacol Ther 85:139–141CrossRefPubMedGoogle Scholar
  13. 13.
    Menashe I, Rosenberg PS, Chen BE (2008) PGA: power calculator for case-control genetic association analyses. BMC Genetics 9:36CrossRefPubMedGoogle Scholar
  14. 14.
    Emmerich F, Bal G, Barakat A, Milz J, Muhle C, Martinez-Gamboa L, Dorner T, Salama A (2007) High-level serum B-cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura. Br J Haematol 136:309–314CrossRefPubMedGoogle Scholar
  15. 15.
    Mo L, Leu SJ, Berry C, Liu F, Olee T, Yang YY, Beardsley DS, McMillan R, Woods VL Jr, Chen PP (1996) The frequency of homozygous deletion of a developmentally regulated Vh gene (Humhv3005) is increased in patients with chronic idiopathic thrombocytopenic purpura. Autoimmunity 24:257–263CrossRefPubMedGoogle Scholar
  16. 16.
    Wu KH, Peng CT, Li TC, Wan L, Tsai CH, Lan SJ, Chang MC, Tsai FJ (2005) Interleukin 4, interleukin 6 and interleukin 10 polymorphisms in children with acute and chronic immune thrombocytopenic purpura. Br J Haematol 128:849–852CrossRefPubMedGoogle Scholar
  17. 17.
    Wu KH, Peng CT, Li TC, Wan L, Tsai CH, Tsai FJ (2007) Interleukin-1beta exon 5 and interleukin-1 receptor antagonist in children with immune thrombocytopenic purpura. J Pediatr Hematol Oncol 29:305–308CrossRefPubMedGoogle Scholar
  18. 18.
    Satoh T, Pandey JP, Okazaki Y, Yasuoka H, Kawakami Y, Ikeda Y, Kuwana M (2004) Single nucleotide polymorphisms of the inflammatory cytokine genes in adults with chronic immune thrombocytopenic purpura. Br J Haematol 124:796–801CrossRefPubMedGoogle Scholar
  19. 19.
    Pavkovic M, Georgievski B, Cevreska L, Spiroski M, Efremov DG (2003) CTLA-4 exon 1 polymorphism in patients with autoimmune blood disorders. Am J Hematol 72:147–149CrossRefPubMedGoogle Scholar
  20. 20.
    Du WT, Zhao HF, Xu JH, Gu DS, Xue F, Ge J, Dong XW, Chen ZP, Zhou ZP, Yang RC (2009) The role of T-cell immunoglobulin- and mucin-domain-containing molecule-3 polymorphisms in idiopathic thrombocytopenic purpura. Hum Immunol 70:398–402CrossRefPubMedGoogle Scholar
  21. 21.
    D'Silva K, Zamora M, Gerlach J, Schwartz KA (2008) PTPN22 mutation is present in an increased proportion of ITP patients. ASH Annual Meeting Abstracts 112:3418Google Scholar
  22. 22.
    Rischewski JR, Wyss J, Stocker S, Hergersberg M, Huber AR, Kuhne T (2008) Rare SOX13 sequence variations in pediatric idiopathic thrombocytopenic purpura patients. ASH Annual Meeting Abstracts 112:3420Google Scholar
  23. 23.
    Xu J, Lu S, Tao J, Zhou Z, Chen Z, Huang Y, Yang R (2008) CD72 polymorphism associated with child-onset of idiopathic thrombocytopenic purpura in Chinese patients. J Clin Immunol 28:214–219CrossRefPubMedGoogle Scholar
  24. 24.
    Foster CB, Zhu S, Erichsen HC, Lehrnbecher T, Hart ES, Choi E, Stein S, Smith MW, Steinberg SM, Imbach P, Kuhne T, Chanock SJ (2001) Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study. Br J Haematol 113:596–599CrossRefPubMedGoogle Scholar
  25. 25.
    Fujimoto TT, Inoue M, Shimomura T, Fujimura K (2001) Involvement of Fc gamma receptor polymorphism in the therapeutic response of idiopathic thrombocytopenic purpura. Br J Haematol 115:125–130CrossRefPubMedGoogle Scholar
  26. 26.
    Carcao MD, Blanchette VS, Wakefield CD, Stephens D, Ellis J, Matheson K, Denomme GA (2003) Fcgamma receptor IIa and IIIa polymorphisms in childhood immune thrombocytopenic purpura. Br J Haematol 120:135–141CrossRefPubMedGoogle Scholar
  27. 27.
    Breunis WB, van Mirre E, Bruin M, Geissler J, de Boer M, Peters M, Roos D, de Haas M, Koene HR, Kuijpers TW (2008) Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood 111:1029–1038CrossRefPubMedGoogle Scholar
  28. 28.
    Williams Y, Lynch S, McCann S, Smith O, Feighery C, Whelan A (1998) Correlation of platelet Fc gammaRIIA polymorphism in refractory idiopathic (immune) thrombocytopenic purpura. Br J Haematol 101:779–782CrossRefPubMedGoogle Scholar
  29. 29.
    Atabay B, Oren H, Irken G, Kizildag S, Tunali S, Turker M, Yilmaz S (2003) Role of transforming growth factor-beta 1 gene polymorphisms in childhood idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol 25:885–889CrossRefPubMedGoogle Scholar
  30. 30.
    Chen Z, Zhou Z, Chen X, Xu J, Liu A, Du W, Gu D, Ge J, Guo Z, Wang X, Dong X, Ren Q, Yang R (2008) Single nucleotide polymorphism in DNMT3B promoter and the risk for idiopathic thrombocytopenic purpura in Chinese population. J Clin Immunol 28:399–404CrossRefPubMedGoogle Scholar
  31. 31.
    Thude H, Gatzka E, Anders O, Barz D (1999) Allele frequencies of human platelet antigen 1, 2, 3, and 5 systems in patients with chronic refractory autoimmune thrombocytopenia and in normal persons. Vox Sang 77:149–153CrossRefPubMedGoogle Scholar
  32. 32.
    Nomura S, Matsuzaki T, Ozaki Y, Yamaoka M, Yoshimura C, Katsura K, Xie GL, Kagawa H, Ishida T, Fukuhara S (1998) Clinical significance of HLA-DRB1*0410 in Japanese patients with idiopathic thrombocytopenic purpura. Blood 91:3616–3622PubMedGoogle Scholar
  33. 33.
    Evers KG, Thouet R, Haase W, Kruger J (1978) HLA frequencies and haplotypes in children with idiopathic thrombocytopenic purpura (ITP). Eur J Pediatr 129:267–272CrossRefPubMedGoogle Scholar
  34. 34.
    Stanworth SJ, Turner DM, Brown J, McCloskey D, Brown C, Provan D, Navarrete CV, Newland AC (2002) Major histocompatibility complex susceptibility genes and immune thrombocytopenic purpura in Caucasian adults. Hematology 7:119–121CrossRefPubMedGoogle Scholar
  35. 35.
    Karpatkin S, Fotino M, Gibofsky A, Winchester RJ (1979) Association of HLA-DRw2 with autoimmune thrombocytopenic purpura. J Clin Invest 63:1085–1088CrossRefPubMedGoogle Scholar
  36. 36.
    el-Khateeb MS, Awidi AS, Tarawneh MS, Abu-Khalaf M (1986) HLA antigens, blood groups and immunoglobulin levels in idiopathic thrombocytopenic purpura. Acta Haematol 76:110–114CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Anke K. Bergmann
    • 1
  • Rachael F. Grace
    • 1
    • 2
  • Ellis J. Neufeld
    • 1
    • 2
  1. 1.Division of Hematology and OncologyChildren’s Hospital Boston and Harvard Medical SchoolBostonUSA
  2. 2.Dana-Farber Cancer InstituteBostonUSA

Personalised recommendations