Gastroenterology
Volume 135, Issue 3 , Pages 830-839.e10 , September 2008

Genetic Variants in Major Histocompatibility Complex-Linked Genes Associate With Pediatric Liver Transplant Rejection

Presented in part at the American Transplant Congress, May 7, 2007, San Francisco, CA.

  • Rakesh Sindhi

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • Corresponding Author InformationAddress requests for reprints to: Rakesh Sindhi, MD, FACS, Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, Pennsylvania 15213. fax: (412) 692-6116
    • ,
  • Brandon W. Higgs

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Daniel E. Weeks

      Affiliations

    • Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Chethan AshokKumar

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Ronald Jaffe

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Cecilia Kim

      Affiliations

    • Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    • ,
  • Patrick Wilson

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Nydia Chien

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Joseph Glessner

      Affiliations

    • Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    • ,
  • Anjan Talukdar

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • George Mazariegos

      Affiliations

    • Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • M. Michael Barmada

      Affiliations

    • Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Edward Frackleton

      Affiliations

    • Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    • ,
  • Nancy Petro

      Affiliations

    • Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
    • ,
  • Andrew Eckert

      Affiliations

    • Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    • ,
  • Hakon Hakonarson

      Affiliations

    • Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
    • ,
  • Robert Ferrell

      Affiliations

    • Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania

Received 21 August 2007 ,Accepted 21 May 2008.

References 

  1. Martin SR, Atkison P, Anand R, et al. SPLIT Research Group Studies of pediatric liver transplantation 2002: patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada. Pediatr Transplant. 2004;8:273–283
  2. Jain A, Mazariegos G, Kashyap R, et al. Pediatric liver transplantation (A single center experience spanning 20 years). Transplantation. 2002;73:941–947
  3. Ireland J, Carlton VEH, Falkowski M, et al. Large-scale characterization of public database SNPs causing non-synonymous changes in three ethnic groups. Hum Genet. 2006;119:75–83
  4. Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–311Available at: www.ncbi.nlm.nih.gov/pubmed/11125122. Accessed July, 2008
  5. Hutchinson IV, Pravica V, Sinnot PJ. Genetic regulation of cytokine synthesis: consequences on acute and chronic organ allograft rejection. Graft. 1998;1:15
  6. Daly AK, Day CP, Donaldson PT. 2002 (Polymorphisms in immunoregulatory genes: toward individualized immunosuppressive therapy?). Am J Pharmacogenomics. 2002;2:13–23
  7. Hirschhorn JN, Lohmueller K, Byrne E, et al. A comprehensive review of genetic association studies. Genet Med. 2002;4:45–61
  8. Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet. 2003;361:598–604
  9. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993;52:506–516
  10. 2007 OPTN/SRTR Annual Report 1997-2006. HHS/HRSA/HSB/DOT.
  11. Hull J, Campino S, Rowlands K, et al. Identification of common genetic variation that modulates alternative splicing. PLoS Genet. 2007;3:e99
  12. Chen Y, Zhu J, Lum PY, et al. Variations in DNA elucidate molecular networks that cause disease. Nature. 2008;452:429–435
  13. Sinsheimer JS, Blangero J, Lange K. 2000. Gamete-competition models. Am J Hum Genet. 2000;66:1168–1172
  14. Ionita-Laza I, McQueen MB, Laird NM, et al. Genome-wide weighted hypothesis testing in family-based association studies, with an application to a 100K scan. Am J Hum Genet. 2007;81:607–614
  15. Shih MC, Whittemore AS. Tests for genetic association using family data. Genet Epidemiol. 2002;22:128–145
  16. Van Steen K, McQueen MB, Herbert A, et al. Genomic screening and replication using the same data set in family-based association testing. Nat Genet. 2005;37:683–691
  17. Sheldon S, Poulton K. HLA typing and its influence on organ transplantation. Methods Mol Biol. 2006;333:157–174
  18. Sindhi R, Magill A, Abdullah A, et al. Enhanced donor-specific alloreactivity occurs independent of immunosuppression in children with early liver allograft rejection. Am J Transplant. 2005;5:96–102
  19. Denzin LK, Sant'Angelo DB, Hammond C, et al. Negative regulation by HLA-DO of MHC class II-restricted antigen processing. Science. 1997;278:106–109
  20. Roucard C, Thomas C, Pasquier MA, et al. In vivo and in vitro modulation of HLA-DM and HLA-DO is induced by B lymphocyte activation. J Immunol. 2001;167:6849–6858
  21. Shen R, Fan JB, Campbell D, et al. High-throughput SNP genotyping on universal bead arrays. Mutat Res. 2002;573:70–82
  22. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am J Hum Genet. Available at: http://pngu.mgh.harvard.edu/purcell/plink/. Accessed July 2008.
  23. Lange K, Cantor R, Horvath S, et al. Mendel version 4.0: a complete package for the exact genetic analysis of discrete traits in pedigree and population data sets. Am J Hum Genet. 2001;69(Suppl):A1886
  24. Srinivasan K, Shiue L, Hayes JD, et al. Detection and measurement of alternative splicing using splicing-sensitive microarrays. Methods. 2005;37:345–359
  25. R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing, Vienna, Austria. Available at: http://www.R-project.org. Accessed July 2008.
  26. The International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437:1299–1320
  27. Zhao T, Chang LW, McLeod HL, et al. PromoLign: a database for upstream region analysis and SNPs. Hum Mutat. 2004;23:534–539
  28. Ge D, Zhang D, Need AC, et al. WGAViewer: a software for genomic annotation of whole genome association studies. Genome Res. 2008;18:640–643
  29. Loiseau P, Esperou H, Busson M, et al. DPB1 disparities contribute to severe GVHD and reduced patient survival after unrelated donor bone marrow transplantation. Bone Marrow Transplant. 2002;30:497–502
  30. Munkhabat B, Hagihara M, Sato T, et al. Association between HLA-DPB1 matching and 1-year rejection-free survival in high-risk corneal transplantation. Transplantation. 1997;63:1011–1016
  31. Mytilineos J, Deufel A, Opelz G. Clinical relevance of HLA-DPB locus matching for cadaver kidney retransplants: a report of the Collaborative Transplant Study. Transplantation. 1997;63:1351–1354
  32. Talukdar A, AshokKumar C, Farrar J, et al. Lymphocyte subset reconstitution in pediatric liver recipients induced with steroid-free rabbit anti-human thymocyte globulin. Pediatr Transplant. 2007;In press. DOI: 10.1111/j.1399-3046.2007.00797.x
  33. Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med. 2003;349:125–138

 Supported by NIH grant 5RO1AI073895-01, Children's Hospital of Pittsburgh Research Foundation, and Hillman Foundation of Pittsburgh.

 Conflicts of interest: None. Study subjects informed.

PII: S0016-5085(08)00955-4

doi: 10.1053/j.gastro.2008.05.080

Gastroenterology
Volume 135, Issue 3 , Pages 830-839.e10 , September 2008

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