Background Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined. Methods and Findings We isolated DNA strands extending across 2 million base pairs of the MHC to determine the physical linkage of HLA-A, -B, and -DRB1 alleles in 246 HCT recipients and their HLA-A, -B, -C, -DRB1, -DQB1 allele-matched unrelated donors. MHC haplotype mismatching was associated with a statistically significantly increased risk of severe acute GVHD (odds ratio 4.51; 95% confidence interval [CI], 2.34–8.70, p < 0.0001) and with lower risk of disease recurrence (hazard ratio 0.45; 95% CI, 0.22–0.92, p = 0.03). Conclusions The MHC harbors genes that encode unidentified transplantation antigens. The three-locus HLA-A, -B, -DRB1 haplotype serves as a proxy for GVHD risk among HLA-identical transplant recipients. The phasing method provides an approach for mapping novel MHC-linked transplantation determinants and a means to decrease GVHD-related morbidity after HCT from unrelated donors.
References
[1]
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, et al. (2002) The structure of haplotype blocks in the human genome. Science 296: 2225–2229.
[2]
Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, et al. (2001) Linkage disequilibrium in the human genome. Nature 411: 199–204.
[3]
Kruglyak L (1999) Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22: 139–144.
[4]
The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437: 1299–1320.
[5]
The MHC Sequencing Consortium (1999) Complete sequence and gene map of the human major histocompatibility complex. Nature 401: 921–923.
[6]
Goldstein DB (2001) Islands of linkage disequilibrium. Nat Genet 29: 109–111.
[7]
Excoffier L, Slatkin M (1995) Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 12: 921–927.
[8]
Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73: 1162–1169.
[9]
Nagel RL, Fabry ME, Pagnier J, Zohoun I, Wajcman H, et al. (1985) Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type. N Engl J Med 312: 880–884.
[10]
Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, et al. (2000) Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A 97: 10483–10488.
[11]
Stengard JH, Clark AG, Weiss KM, Kardia S, Nickerson DA, et al. (2002) Contributions of 18 additional DNA sequence variations in the gene encoding apolipoprotein E to explaining variation in quantitative measures of lipid metabolism. Am J Hum Genet 71: 501–517.
[12]
Mallal S, Nolan D, Witt C, Masel G, Martin AM, et al. (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359: 727–732.
[13]
Yunis EJ, Larsen CE, Fernandez-Vina M, Awdeh ZL, Romero T, et al. (2003) Inheritable variable sizes of DNA stretches in the human MHC: Conserved extended haplotypes and their fragments or blocks. Tissue Antigens 62: 1–20.
[14]
Miretti MM, Walsh EC, Ke X, Delgado M, Griffiths M, et al. (2005) A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 76: 634–646.
[15]
Malkki M, Single R, Carrington M, Thomson G, Petersdorf E (2005) MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: Implications for unrelated donor hematopoietic transplantation and disease association studies. Tissue Antigens 66: 114–124.
[16]
Stewart CA, Horton R, Allcock RJ, Ashurst JL, Atrazhev AM, et al. (2004) Complete MHC haplotype sequencing for common disease gene mapping. Genome Res 14: 1176–1187.
[17]
Walsh EC, Mather KA, Schaffner SF, Farwell L, Daly MJ, et al. (2003) An integrated haplotype map of the human major histocompatibility complex. Am J Hum Genet 73: 580–590.
[18]
Degli-Esposti MA, Leaver AL, Christiansen FT, Witt CS, Abraham LJ, et al. (1992) Ancestral haplotypes: Conserved population MHC haplotypes. Hum Immunol 34: 242–252.
[19]
Traherne JA, Horton R, Roberts AN, Miretti MM, Hurles ME, et al. (2006) Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history. PLoS Genet 2: e9.. doi:10.1371/journal.pgen.0020009.
[20]
Ahmad T, Neville M, Marshall SE, Armuzzi A, Mulcahy-Hawes K, et al. (2003) Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. Hum Mol Genet 12: 647–656.
[21]
Aly TA, Eller E, Ide A, Gowan K, Babu SR, et al. (2006) Multi-SNP analysis of MHC region: Remarkable conservation of HLA-A1-B8-DR3 haplotype. Diabetes 55: 1265–1269.
[22]
Price P, Witt C, Allcock R, Sayer D, Garlepp M, et al. (1999) The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev 167: 257–274.
[23]
Shiina T, Inoko H, Kulski JK (2004) An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 64: 631–649.
[24]
Ketheesan N, Gaudieri S, Witt CS, Tay GK, Townend DC, et al. (1999) Reconstruction of the block matching profiles. Hum Immunol 60: 171–176.
[25]
Todd JA, Farrall M (1996) Panning for gold: Genome-wide scanning for linkage in type 1 diabetes. Hum Mol Genet 5: 1443–1448.
[26]
Allcock RJ, Atrazhev AM, Beck S, de Jong PJ, Elliott JF, et al. (2002) The MHC haplotype project: A resource for HLA-linked association studies. Tissue Antigens 59: 520–521.
[27]
Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM (2000) Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med 343: 1078–1084.
[28]
Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, et al. (1998) Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. N Engl J Med 339: 1177–1185.
[29]
Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, et al. (2004) Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood 104: 1923–1930.
[30]
Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, et al. (2001) Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. N Engl J Med 345: 1794–1800.
[31]
Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, et al. (2004) Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood 104: 3501–3506.
[32]
Guo Z, Hood L, Malkki M, Petersdorf EW (2006) Long-range multilocus haplotype phasing of the MHC. Proc Natl Acad Sci U S A 103: 6964–6969.
[33]
Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, et al. (1998) Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 92: 3515–3520.
[34]
Petersdorf EW, Anasetti C, Martin PJ, Gooley T, Radich J, et al. (2004) Limits of HLA mismatching in unrelated hematopoietic cell transplantation. Blood 104: 2976–2980.
[35]
Tishkoff SA, Pakstis AJ, Ruano G, Kidd KK (2000) The accuracy of statistical methods for estimation of haplotype frequencies: An example from the CD4 locus. Am J Hum Genet 67: 518–522.
[36]
Ding C, Cantor CR (2003) Direct molecular haplotyping of long-range genomic DNA with M1-PCR. Proc Natl Acad Sci U S A 100: 7449–7453.
[37]
Anasetti C, Beatty PG, Storb R, Martin PJ, Mori M, et al. (1990) Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol 29: 79–91.
[38]
Petersdorf EW, Malkki M (2005) Human leukocyte antigen matching in unrelated donor hematopoietic cell transplantation. Semin Hematol 42: 76–84.
[39]
Perreault C, Decary F, Brochu S, Gyger M, Belanger R, et al. (1990) Minor histocompatibility antigens. Blood 76: 1269–1280.
[40]
Hsu KC, Dupont B (2005) Natural killer cell receptors: Regulating innate immune responses to hematologic malignancy. Semin Hematol 42: 91–103.
[41]
Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, et al. (2005) Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 23: 1993–2003.
[42]
Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, et al. (2004) Gene map of the extended human MHC. Nat Rev Genet 5: 889–899.
[43]
Kollman C, Abella E, Baitty RL, Beatty PG, Chakraborty R, et al. (2004) Assessment of optimal size and composition of the U.S. National Registry of hematopoietic stem cell donors. Transplantation 78: 89–95.
[44]
Schipper RF, D'Amaro J, Bakker JT, Bakker J, van Rood JJ, et al. (1997) HLA gene haplotype frequencies in bone marrow donors worldwide registries. Hum Immunol 52: 54–71.
[45]
Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, et al. (2001) Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 29: 223–228.
[46]
Carrington M, Nelson GW, Martin MP, Kissner T, Vlahov D, et al. (1999) HLA and HIV-1: Heterozygote advantage and B*35-Cw*04 disadvantage. Science 283: 1748–1752.
[47]
Reich D, Patterson N, De Jager PL, McDonald GJ, Waliszewska A, et al. (2005) A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility. Nat Genet 37: 1113–1118.
