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HLA & Leukemia Associations: What do they mean? M. Tevfik DORAK Environmental & Occupational Health College of P

HLA & Leukemia Associations: What do they mean? M. Tevfik DORAK Environmental & Occupational Health College of Public Health Florida International University Miami, USA http://www.dorak.info - Why leukamia, why HLA? - Unravelling HLA associations? - What do they mean?

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HLA & Leukemia Associations: What do they mean? M. Tevfik DORAK Environmental & Occupational Health College of P

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  1. HLA & Leukemia Associations: What do they mean? M. Tevfik DORAK Environmental & Occupational Health College of Public Health Florida International University Miami, USA http://www.dorak.info

  2. - Why leukamia, why HLA? - Unravelling HLA associations? - What do they mean? - HLA or MHC - LD?

  3. Human Major Histocompatibility Complex - HLA Complex - Cooke & Hill. Nature Rev Genet2001 (www)

  4. DRB1*01 DRB1*15/16 DRB1*03 DRB1*04 DRB1*11/12 DRB1*13/14 DRB1*07 DRB1*08 DRB1*09 DRB1*10 DRB1 DRB5 DRB3 DRB4 Expressed HLA-DRB gene content of HLA class II haplotypes (second DRB gene determines the ancestral lineage)

  5. DRB4 / DRB5 / DRB1*01/10 DRB3 / DRB1*08 Klein, 1990 (www)

  6. DRB3 / DRB1*08 DRB4 / DRB5 / DRB1*01/10 Ayala, 1994 (www)

  7. (www)

  8. HLA-DRB3 and -DRB4 haplotypes represent ancestral lineages of contemporary MHC haplotypes See Kennedy, Singh & Dorak, 2012 for DRB4 lineage-specific SNP rs2395185: http://jnci.oxfordjournals.org/content/104/11/884.long

  9. Unintentional Evolutionary-Based Haplotype Analysis

  10. Search for a Leukemia Susceptibility Gene in the HLA Complex Chronic Myeloid Leukemia (CML): Scotland and Turkey Chronic Lymphoid Leukemia (CLL): Germany Childhood Acute Lymphoblastic Leukemia (ALL): Wales, Scotland and Turkey All showed some form of HLA-DRB4 (DR53) association

  11. Why Leukemia?

  12. Inbred mouse strains are homozygous for H-2 haplotypes Heterozygosity for the susceptibility haplotype did not have an effect

  13. Spontaneous leukemia shows the same association

  14. Dorak et al, 1994 (www)

  15. Conventional analysis shows no association even with homozygosity

  16. Stratification by age revealed associations

  17. P = 0.02 DR53 homozygosity was a risk marker (P = 0.01; OR = 3.36) and DR52 homozygosity was protective (P = 0.007; OR = 0.51). Oguz et al, 2003 (www) (PDF)

  18. Dorak et al, 1996 (www)

  19. Reminder: Mouse H-2 Studies

  20. Dorak et al, 1999 (www)

  21. Globocan 2002, IARC (www)

  22. Globocan 2002, IARC (www)

  23. Leukemia is more frequent in males and in developed countries

  24. Cartwright RA et al. Sex ratios and the risks of haematological malignancies. BJH 2002 (www)

  25. xMHC Loci Analysed in Childhood ALL 6p21.3 - 24.1 EDN1 HSPA1B LTA HLA-DRB1 HLA-DRB3/4/5 HLA-Bw HFE BF TNF HLA CLASS III REGION

  26. Conventional Analysis

  27. Conventional Analysis

  28. HLA-DRB4 Association in Childhood ALL Homozygosity for HLA-DRB4 family is associated with susceptibility to childhood ALL in boys only (P < 0.0001, OR = 6.1, 95% CI = 2.9 to 12.6) Controls are an unselected group of local newborns (201 boys & 214 girls) * Case-only analysis P = 0.002 (OR = 5.6; 95% CI = 1.8 to 17.6) This association extends to a DRB4-HSP70 haplotype (OR = 8.3; 95% CI = 3.0 to 22.9) This association has been replicated in Scotland and Turkey % % * Girls, n=53 Boys, n=64 * Dorak et al, 1999 (www)

  29. HLA-DRB4 ASSOCIATION ADDITIVE MODEL Linear Model Logit estimates Number of obs = 265 LR chi2(1) = 14.24 Prob > chi2 = 0.0002 Log likelihood = -139.37794 Pseudo R2 = 0.0486 ------------------------------------------------------------------------------ caco | Common Odds Ratio Std. Err. z P>|z| [95% CI] -------------+---------------------------------------------------------------- drb4add | 2.208651 .4734163 3.70 0.000 1.45103 - 3.36186 ------------------------------------------------------------------------------ Heterozygosity and Homozygosity Logit estimates Number of obs = 265 LR chi2(2) = 22.00 Prob > chi2 = 0.0000 Log likelihood = -135.49623 Pseudo R2 = 0.0751 ------------------------------------------------------------------------------ caco | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- Wild-type | 1.00 (ref) Heterozygosity | 1.060652 .3557426 0.18 0.861 .549642 2.04676 Homozygosity | 6.258503 2.65464 4.32 0.000 2.72534 14.37211 ------------------------------------------------------------------------------

  30. HLA-DRB4 - HSPA1B HAPLOTYPE ASSOCIATION EFFECT MODIFICATION Logit estimates Number of obs = 532 LR chi2(3) = 23.97 Prob > chi2 = 0.0000 Log likelihood = -268.27826 Pseudo R2 = 0.0428 ------------------------------------------------------------------------------ caco | Coef. Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- sex | -.0299037 .2229554 -0.13 0.893 -.4668883 .4070808 hsp53 | 2.530033 .5929603 4.27 0.000 1.367852 3.692214 _IsexXhsp5~2 | -2.758189 .8812645 -3.13 0.002 -4.485436 -1.030943 _cons | -1.321474 .3517969 -3.76 0.000 -2.010984 -.6319651 ------------------------------------------------------------------------------ CONFOUNDING BY SEX Logit estimates Number of obs = 532 LR chi2(2) = 11.99 Prob > chi2 = 0.0025 Log likelihood = -274.26995 Pseudo R2 = 0.0214 ------------------------------------------------------------------------------ caco | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- hsp53 | 3.32777 1.191429 3.36 0.001 1.649684 6.712832 sex | .7693041 .1636106 -1.23 0.218 .5070725 1.167148 ------------------------------------------------------------------------------ Adjusted for sex?

  31. HLA-DRB4 - HSPA1B HAPLOTYPE ASSOCIATION BOYS ONLY Logit estimates Number of obs = 265 LR chi2(1) = 22.41 Prob > chi2 = 0.0000 Log likelihood = -135.29119 Pseudo R2 = 0.0765 ------------------------------------------------------------------------------ caco | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- hsp53 | 12.55392 7.444028 4.27 0.000 3.926876 40.13392 ------------------------------------------------------------------------------ GIRLS ONLY Logit estimates Number of obs = 267 LR chi2(1) = 0.13 Prob > chi2 = 0.7205 Log likelihood = -132.98706 Pseudo R2 = 0.0005 ------------------------------------------------------------------------------ caco | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- hsp53 | 0.796 .5189439 -0.35 0.726 .22181 2.856571 ------------------------------------------------------------------------------ The association is modified by sex…

  32. HFE-C282Y Association in Childhood ALL % % WELSH GROUP 117 patients - 415 newborns P = 0.005; OR = 2.8 (1.4 to 5.4) In cALL: P = 0.02; OR = 2.9 (1.4 to 6.4) SCOTTISH GROUP 135 patients - 238 newborns P = 0.0004; OR = 3.0 (1.7 to 5.4) In cALL: P < 0.0001;OR = 4.7 (2.5 to 8.9) Dorak et al, 1999 (www)

  33. EDN1 Association in Childhood ALL Preliminary findings % In a preliminary study in childhood ALL, EDN1 STR 207 bp allele (A6) frequency is increased in males (P = 0.004; OR = 4.5, 95% CI = 1.6 to 13.0)

  34. Final Multivariable Logistic Regression Model (boys) Logit estimates Number of obs = 265 LR chi2(2) = 26.68 Prob > chi2 = 0.0000 Log likelihood = -133.15366 Pseudo R2 = 0.0911 ------------------------------------------------------------------------------ caco | Odds Ratio Std. Err. z P>|z| [95% Conf. Interval] -------------+---------------------------------------------------------------- hsp53 | 12.90181 7.713223 4.28 0.000 3.99731 41.64217 hfe-c282y | 2.25126 .860627 2.12 0.034 1.064196 4.762431 ------------------------------------------------------------------------------ Attributable fraction for HLA-DRB4 - HSPA1B association: 15.2% (95% CI = 8.6 to 21.3) Attributable fraction for HFE - C282Y association : 8.8% (95% CI = 0.0 to 17.4) 1 in 3 boys with ALL are homozygote for the ancestral DRB4 haplotype and 1 in 4 boys are positive for the HFE-C282Y mutation

  35. Despite the obvious effect modification by sex, and recessive nature of most MHC associations in childhood leukemia, old habits are maintained and most studies only compare all cases with all controls, and using only one genetic model. And, find nothing!

  36. Possible Mechanisms of HLA-DRB4 Associations in Childhood ALL Spurious Population stratification, bias, chance Causal I (immunological) HLA-DRB4 family of haplotypes are functionally suboptimal in their antigen presentation role Causal I (genetical) Linkage disequilibrium with non-HLA genes has to be ruled out

  37. Possible Mechanisms of HLA-DRB4 Associations in Childhood ALL Spurious Population stratification, bias, chance Current Childhood ALL Case-Control Set Genomic Control Replication Gene x Gene Interactions (Tyneside Leukaemia Research Association funding secured)

  38. Possible Mechanisms of HLA-DRB4 Association in Childhood ALL HLA-DRB4 family of haplotypes are functionally suboptimal in their antigen presentation role

  39. HLA-DRB4 family of haplotypes are functionally suboptimal in their antigen presentation role Immune nonresponsiveness is a recessive trait Supported by association with homozygosity and association in boys

  40. HLA-DRB4 family of haplotypes are functionally suboptimal in their antigen presentation role HLA-DRB4 family of haplotypes express DRB1 and DRB4 genes at a lower level Louis, 1994 (www); Vincent, 1996 (www) & 1997 (www) The lowest cumulative expression of HLA-DRB genes (even lower in homozygotes) may result in: - DRa-DQb mixed isotype heterodimer formation - Aberrant T-cell response and autoimmune reactions Charron, 1984 (www); Lotteau, 1987 (www) & 1989 (www); Matsunaga, 1990 (www); Spencer 1989 (www) & 1992 (www) & 1993 (www) Supported by association with homozygosity

  41. HLA-DRB4 family of haplotypes are functionally suboptimal in their antigen presentation role HLA-DR53 interacts poorly with CD4 (www) Supported by association with homozygosity

  42. HLA-DRB4 family of haplotypes are functionally suboptimal in their antigen presentation role HLA-DRB1 residue 81 substitution severely affects intracellular transport of the mutant DRb chain Chervonsky, 1994 (www) HLA-DRB4 residue 81 is naturally different from that of all other DRB1/3/5 molecules

  43. HLA-DRB4 family of haplotypes may be involved in susceptibility through molecular mimicry HLA-DRB4 HVR3 epitope (LLERRRAE) is mimicked in its entirety by adenovirus and EBV Dorak et al, 1994 (www)

  44. HLA-DRB4 family of haplotypes may be involved in susceptibility through molecular mimicry Anti-HLA autoantibodies are present in other infectious diseases due to molecular mimicry Dorak et al, 1996 (www)

  45. Dorak et al, 1996 (www)

  46. Possible Mechanisms of HLA-DRB4 Associations in Childhood ALL Spurious Population stratification, bias, chance Causal I (immunological) HLA-DRB4 family of haplotypes are functionally suboptimal in their antigen presentation role Causal II (genetical) Linkage disequilibrium with non-HLA genes has to be ruled out

  47. Human Major Histocompatibility Complex - simple map - Cooke & Hill. Nature Rev Genet2001 (www)

  48. Human Major Histocompatibility Complex Most gene-dense region in the genome Xie, 2003(www)

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