title: HLA system affects the age-at-onset in chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) occurs from childhood to old age. The adult form is characterized by the presence of Philadelphia chromosome resulting from bcr/abl translocation. The BCR-ABL fusion proteins are immunogenic, and the junctional sequences show unique HLA class I and class II restriction patterns in vitro. A previous study in the west of Scotland showed an influence of several HLA genotypes on the age-at-onset of CML. In the present study, we examined the HLA-A, -B, and -DRB1/3/4/5 allele and haplotype distributions in Turkish CML patients diagnosed in a single center where they are routinely HLA-typed by PCR-SSP analysis as a preparation for stem cell transplantation. The patients were 169 subjects of age 17-60 years. The older patients were not HLA typed and missing from the study group. The age-matched control group (n = 213) was healthy blood donors from the same geographical area. HLA-B*37 showed a risk association with CML [P = 0.02; odds ratio (OR) = 5.35]. The DRB1*10 association at similar magnitude was due to its linkage disequilibrium (LD) with B*37. HLA-B*35 and DRB1*11 showed independent protective effects (P = 0.007 and 0.017; OR = 0.54 and 0.60, respectively). The protective association of DRB1*11 may be due to its involvement in the presentation of the common (b3a2) fusion gene. HLA-B*14 and DRB1*01 showed strong LD, and all 5 patients who were positive for the presumed haplotype B*14-DRB1*01 were of age 43 years old or older (P = 0.003), suggesting a delay effect. We also examined the influence of homozygosity for DRB3 (DR52) and DRB4 (DR53) haplotypes on susceptibility. As previously shown in CML and CLL, DRB4 homozygosity was a risk marker (P = 0.01; OR = 3.36), and DRB3 homozygosity was protective (P = 0.007; OR = 0.51). Despite the lack of elderly patients in the study group, the opposite accelerating (DRB4) and delaying (DRB3) effects of homozygous genotypes on the age-at-onset were evident. Besides replicating previously found associations in a different population, this study also suggested new, and probably population-specific associations in CML. The mechanisms by which the HLA system modifies susceptibility to CML are unknown, likely to include immune and nonimmune ones, and worthy of further studies.
authors.affiliation: Department of Medical Biology, Istanbul University, Istanbul Medical School, Istanbul, Turkey.
authors.forename: Fatma Savran
authors.initials: FS
authors.lastname: Oguz
authors.forename: Sevgi
authors.initials: S
authors.lastname: Kalayoglu
authors.forename: A Sarper
authors.initials: AS
authors.lastname: Diler
authors.forename: Hilmi
authors.initials: H
authors.lastname: Tozkir
authors.forename: Deniz
authors.initials: D
authors.lastname: Sargin
authors.forename: Mahmut
authors.initials: M
authors.lastname: Carin
authors.forename: M Tevfik
authors.initials: MT
authors.lastname: Dorak
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006680:HLA Antigens / Q000235:genetics*; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006720:Homozygote; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D016017:Odds Ratio; D012189:Retrospective Studies; D014421:Turkey / Q000453:epidemiology
chemical_list: D006680:HLA Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains