Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis was tested that amino acid substitutions in specific positions within human leukocyte antigen class I heavy chain would have different impacts on transplant-related mortality (TRM) in patients receiving transplanted bone marrow from unrelated donors. One hundred patients and their unrelated donors were typed by sequence-based typing for the human leukocyte antigen (HLA)-A, -B, and -C loci. All pairs were matched for DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 loci. Forty pairs were also matched at class I, and 60 pairs had one or more mismatches at class I loci. It was found that substitutions at positions 116 and 114 of class I heavy chain significantly increased the risk for TRM in univariate and bivariate Cox analyses. Conversely, no association between number of multiple mismatches or number of amino acid substitutions and TRM was seen when positions 116 and 114 were adjusted for. Variables predictive of TRM in multivariate Cox analysis were number of cells infused, diagnosis (chronic myeloid leukemia [CML] or non-CML), and amino acid substitution at position 116 or 152. The only variable predictive of severe acute graft-versus-host disease (GVHD) in multivariate Cox analysis was substitution at position 116. Actuarial risk for acute GVHD grade III-IV, TRM, and relapse in pairs with substitutions at position 116 (n = 37) compared to other pairs (n = 63) was, respectively, 36% versus 14% (P =.01), 59% versus 28% (P =.001), and 25% versus 31% (P =.4). In conclusion these data suggest that substitutions at position 116 of class I heavy chain increase the risk for acute GVHD and TRM in patients who receive transplanted bone marrow from unrelated donors.
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PMID:Bone marrow transplantation from unrelated donors: the impact of mismatches with substitutions at position 116 of the human leukocyte antigen class I heavy chain. 1169 4

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.
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PMID:HLA system affects the age-at-onset in chronic myeloid leukemia. 1287 29