1 Leukemia 2012 Vol: 27(1):255-258. DOI: 10.1038/leu.2012.173

Risk of developing chronic lymphocytic leukemia is influenced by HLA-A class I variation

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.

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Figures
Figure 1: Association between SNPs and haplotypes mapping to 6p21 and CLL risk. The x axis represents the position of each SNP, and the y axis depicts P values on a minus logarithmic scale. Cochran–Armitage trend test statistics are shown in gray for directly genotyped SNPs in the top panel. Lines in the bottom panel correspond to haplotype test statistics: gray defined by 5 SNPs and black by 13 SNPs. Relative positions of the major HLA genes are also shown. Chromosomal coordinates derived from the National Center for Biotechnology Information, build 36.
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References
  1. Sellick GS, Catovsky D, Houlston RS. Familial chronic lymphocytic leukemia. Semin Oncol 2006; 33: 195-201 , .
    • . . . The increased risk of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) in relatives of CLL patients suggests a common etiology to B-cell lymphoproliferative disorders (LPDs) through HLA variation.1 Moreover, as B-cell proliferation is part of an adaptive immune response, which can be initiated by major histocompatibility complex (MHC)-restricted T-cell activation, a possible influence of HLA on CLL pathogenesis is plausible. . . .
  2. Leslie S, Donnelly P, McVean G. A statistical method for predicting classical HLA alleles from SNP data. Am J Hum Genet 2008; 82: 48-56 , .
    • . . . It has recently been demonstrated that single nucleotide polymorphism (SNP) variation within the 6p21 region can accurately predict alleles at HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQA1 and HLA-DQB1 loci.2 Furthermore, HLA alleles can be accurately predicted from the SNPs used in a genome-wide association study (GWAS) . . .
    • . . . To survey the relationship between HLA alleles and CLL risk, we predicted class I and II HLA alleles using HLA*IMP software (version 1.3) making use of a reference database from the HapMap Project and 58BC controls.2 To ensure prediction accuracy, we only analyzed alleles that were predicted with a posterior probability >90%, and this criterion was met by >88% of the data . . .
  3. Di Bernardo MC, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R et al. A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet 2008; 40: 1204-1210 , .
    • . . . The 517 CLL cases (364 male) analyzed in the GWAS have been previously documented.3 Briefly, they comprised 155 CLL cases with a relative affected with CLL or a related B-cell LPD ascertained through the International CLL linkage consortium (ICLLLC) and 362 cases ascertained through the Leukemia Research CLL4 trial . . .
    • . . . The genome-wide SNP scan was conducted using Illumina Infinium HD Human370 Duo BeadChips.3 For controls we made use of genotype data generated by the Wellcome Trust Case Control Consortium on 2930 individuals from the British 1958 Birth Cohort (58BC) . . .
    • . . . After imposing rigorous quality control in terms of excluding samples and SNPs with poor call rates and SNPs showing significant departure from Hardy–Weinberg equilibrium, samples showing evidence of relatedness and ancestral differences,3 SNP genotypes were available on 503 cases and 2698 controls. . . .
    • . . . In terms of impact, HLA variation has a weaker effect on CLL risk than the recently identified non-HLA loci;3 this is in stark contrast to HL, a disease which is primarily defined by HLA.15 Finally, although speculative, the reciprocal HLA-A*02 associations seen for HL and CLL raise the possibility of differential response to viral infection, such as EBV, also playing a role in the development of CLL. . . .
  4. Slager SL, Rabe KG, Achenbach SJ, Vachon CM, Goldin LR, Strom SS et al. Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL. Blood 2011; 117: 1911-1916 , .
    • . . . A recent GWAS of CLL reported an association with SNPs mapping to HLA-DRB5 and HLA-DQA1 loci.4 In our study, the best evidence for an association at this region was provided by rs660895, which maps to 32 685 358 bp (P=0.09) and HLA-DRB*1101 (P=0.038, Supplementary Table 2). . . .
    • . . . The recent GWAS of CLL reported by Slager et al.4 found an association between SNPs mapping to the 6p21.32 region, which encompasses the HLA-DQA1 and HLA-DRB5 genes . . .
  5. Crowther-Swanepoel D, Wild R, Sellick G, Dyer MJ, Mauro FR, Cuthbert RJ et al. Insight into the pathogenesis of chronic lymphocytic leukemia (CLL) through analysis of IgVH gene usage and mutation status in familial CLL. Blood 2008; 111: 5691-5693 , .
    • . . . To examine whether carrier status for HLA-A*0201 was associated with a restricted immunoglobulin gene usage, we made use of previously generated data on CLL4 cases.5 Although immunoglobulin heavy chain variable region (IGHV) usage was non-random, with VH3, VH1 and VH4 families expressed at the highest frequencies (50%, 27% and 15% respectively, Supplementary Table 3), globally there was no difference in usage of specific VH subtypes by HLA-A*0201 genotype in the cases after correction for multiple testing. . . .
    • . . . It is intriguing that the association was confined to familial CLL cases as familial disease is essentially indistinguishable from CLL.5 The region has been recently identified to harbor variants associated with other B-cell malignancies, including follicular lymphoma and diffuse large B-cell lymphoma.13, 14 As familial aggregation of CLL and NHL is shown, the 6p21.32 association could be reflective of common genetic susceptibility to a range of B-cell LPDs . . .
  6. Damle RN, Calissano C, Chiorazzi N. Chronic lymphocytic leukaemia: a disease of activated monoclonal B cells. Best Pract Res Clin Haematol Mar 23: 33-45 , .
    • . . . In addition, in the context of T cell cross-talk, CD4+ T-cells in CLL have been identified in the pseudofollicle/proliferation centers on the tissues involved, and their physical contact with CLL cells suggests an important role in the activation and survival of CLL cells.6 A role for the HLA-A*02 allele in evoking an effective immune response is supported by the observation that HLA-A*02 is associated with reduced persistence of hepatitis B viral infection7 and the finding of an underrepresentation of HLA-A*02 in patients with tuberculosis.8 The HLA-A*02 allele has also been consistently shown to afford protection against multiple sclerosis.9 HL displays a strong HLA class I association, with underrepresentation of HLA-A*02 associated with Epstein-Barr virus (EBV)-positive disease.10 Intriguingly, in a recent GWAS of HL in the MHC region, rs6904029 provided one of the strongest SNP associations for EBV-positive HL, the A-allele conferring an OR of 0.46.11 Following EBV infection, infected memory B-cells escape immune detection by downregulation of viral antigens . . .
  7. Zhang SY, Gu HX, Li D, Yang SF, Zhong ZH, Li XK et al. Association of human leukocyte antigen polymorphism with hepatitis B virus infection and genotypes. Jpn J Infect Dis 2006; 59: 353-357 , .
    • . . . In addition, in the context of T cell cross-talk, CD4+ T-cells in CLL have been identified in the pseudofollicle/proliferation centers on the tissues involved, and their physical contact with CLL cells suggests an important role in the activation and survival of CLL cells.6 A role for the HLA-A*02 allele in evoking an effective immune response is supported by the observation that HLA-A*02 is associated with reduced persistence of hepatitis B viral infection7 and the finding of an underrepresentation of HLA-A*02 in patients with tuberculosis.8 The HLA-A*02 allele has also been consistently shown to afford protection against multiple sclerosis.9 HL displays a strong HLA class I association, with underrepresentation of HLA-A*02 associated with Epstein-Barr virus (EBV)-positive disease.10 Intriguingly, in a recent GWAS of HL in the MHC region, rs6904029 provided one of the strongest SNP associations for EBV-positive HL, the A-allele conferring an OR of 0.46.11 Following EBV infection, infected memory B-cells escape immune detection by downregulation of viral antigens . . .
  8. Souza CF, Noguti EN, Visentainer JE, Cardoso RF, Petzl-Erler ML, Tsuneto LT. HLA and MICA genes in patients with tuberculosis in Brazil. Tissue Antigens 2012; 79: 58-63 , .
    • . . . In addition, in the context of T cell cross-talk, CD4+ T-cells in CLL have been identified in the pseudofollicle/proliferation centers on the tissues involved, and their physical contact with CLL cells suggests an important role in the activation and survival of CLL cells.6 A role for the HLA-A*02 allele in evoking an effective immune response is supported by the observation that HLA-A*02 is associated with reduced persistence of hepatitis B viral infection7 and the finding of an underrepresentation of HLA-A*02 in patients with tuberculosis.8 The HLA-A*02 allele has also been consistently shown to afford protection against multiple sclerosis.9 HL displays a strong HLA class I association, with underrepresentation of HLA-A*02 associated with Epstein-Barr virus (EBV)-positive disease.10 Intriguingly, in a recent GWAS of HL in the MHC region, rs6904029 provided one of the strongest SNP associations for EBV-positive HL, the A-allele conferring an OR of 0.46.11 Following EBV infection, infected memory B-cells escape immune detection by downregulation of viral antigens . . .
  9. Bergamaschi L, Leone MA, Fasano ME, Guerini FR, Ferrante D, Bolognesi E et al. HLA-class I markers and multiple sclerosis susceptibility in the Italian population. Genes Immun 2011; 11: 173-180 , .
    • . . . In addition, in the context of T cell cross-talk, CD4+ T-cells in CLL have been identified in the pseudofollicle/proliferation centers on the tissues involved, and their physical contact with CLL cells suggests an important role in the activation and survival of CLL cells.6 A role for the HLA-A*02 allele in evoking an effective immune response is supported by the observation that HLA-A*02 is associated with reduced persistence of hepatitis B viral infection7 and the finding of an underrepresentation of HLA-A*02 in patients with tuberculosis.8 The HLA-A*02 allele has also been consistently shown to afford protection against multiple sclerosis.9 HL displays a strong HLA class I association, with underrepresentation of HLA-A*02 associated with Epstein-Barr virus (EBV)-positive disease.10 Intriguingly, in a recent GWAS of HL in the MHC region, rs6904029 provided one of the strongest SNP associations for EBV-positive HL, the A-allele conferring an OR of 0.46.11 Following EBV infection, infected memory B-cells escape immune detection by downregulation of viral antigens . . .
  10. Niens M, Jarrett RF, Hepkema B, Nolte IM, Diepstra A, Platteel M et al. HLA-A*02 is associated with a reduced risk and HLA-A*01 with an increased risk of developing EBV+ Hodgkin lymphoma. Blood 2007; 110: 3310-3315 , .
    • . . . In addition, in the context of T cell cross-talk, CD4+ T-cells in CLL have been identified in the pseudofollicle/proliferation centers on the tissues involved, and their physical contact with CLL cells suggests an important role in the activation and survival of CLL cells.6 A role for the HLA-A*02 allele in evoking an effective immune response is supported by the observation that HLA-A*02 is associated with reduced persistence of hepatitis B viral infection7 and the finding of an underrepresentation of HLA-A*02 in patients with tuberculosis.8 The HLA-A*02 allele has also been consistently shown to afford protection against multiple sclerosis.9 HL displays a strong HLA class I association, with underrepresentation of HLA-A*02 associated with Epstein-Barr virus (EBV)-positive disease.10 Intriguingly, in a recent GWAS of HL in the MHC region, rs6904029 provided one of the strongest SNP associations for EBV-positive HL, the A-allele conferring an OR of 0.46.11 Following EBV infection, infected memory B-cells escape immune detection by downregulation of viral antigens . . .
  11. Urayama KY, Jarrett RF, Hjalgrim H, Diepstra A, Kamatani Y, Chabrier A et al. Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. J Natl Cancer Inst 2012; 104: 240-253 , .
    • . . . In addition, in the context of T cell cross-talk, CD4+ T-cells in CLL have been identified in the pseudofollicle/proliferation centers on the tissues involved, and their physical contact with CLL cells suggests an important role in the activation and survival of CLL cells.6 A role for the HLA-A*02 allele in evoking an effective immune response is supported by the observation that HLA-A*02 is associated with reduced persistence of hepatitis B viral infection7 and the finding of an underrepresentation of HLA-A*02 in patients with tuberculosis.8 The HLA-A*02 allele has also been consistently shown to afford protection against multiple sclerosis.9 HL displays a strong HLA class I association, with underrepresentation of HLA-A*02 associated with Epstein-Barr virus (EBV)-positive disease.10 Intriguingly, in a recent GWAS of HL in the MHC region, rs6904029 provided one of the strongest SNP associations for EBV-positive HL, the A-allele conferring an OR of 0.46.11 Following EBV infection, infected memory B-cells escape immune detection by downregulation of viral antigens . . .
  12. Bei JX, Li Y, Jia WH, Feng BJ, Zhou G, Chen LZ et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat Genet 2010; 42: 599-603 , .
    • . . . The CLL association with HLA-A*0201 is, however, analogous to that shown in nasopharyngeal carcinoma (NPC), whereby an increased risk of NPC is associated with HLA-A*0201 carrier status.12 The non-random usage of variable domain elements of IGHV provides evidence of selection by chronic antigen stimulation or selection through the B-cell receptor . . .
  13. Skibola CF, Bracci PM, Halperin E, Conde L, Craig DW, Agana L et al. Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat Genet 2009; 41: 873-875 , .
    • . . . It is intriguing that the association was confined to familial CLL cases as familial disease is essentially indistinguishable from CLL.5 The region has been recently identified to harbor variants associated with other B-cell malignancies, including follicular lymphoma and diffuse large B-cell lymphoma.13, 14 As familial aggregation of CLL and NHL is shown, the 6p21.32 association could be reflective of common genetic susceptibility to a range of B-cell LPDs . . .
  14. Conde L, Halperin E, Akers NK, Brown KM, Smedby KE, Rothman N et al. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat Genet 2010; 42: 661-664 , .
    • . . . It is intriguing that the association was confined to familial CLL cases as familial disease is essentially indistinguishable from CLL.5 The region has been recently identified to harbor variants associated with other B-cell malignancies, including follicular lymphoma and diffuse large B-cell lymphoma.13, 14 As familial aggregation of CLL and NHL is shown, the 6p21.32 association could be reflective of common genetic susceptibility to a range of B-cell LPDs . . .
  15. Enciso-Mora V, Broderick P, Ma Y, Jarrett RF, Hjalgrim H, Hemminki K et al. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 2010; 42: 1126-1130 , .
    • . . . In terms of impact, HLA variation has a weaker effect on CLL risk than the recently identified non-HLA loci;3 this is in stark contrast to HL, a disease which is primarily defined by HLA.15 Finally, although speculative, the reciprocal HLA-A*02 associations seen for HL and CLL raise the possibility of differential response to viral infection, such as EBV, also playing a role in the development of CLL. . . .
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