title: Allele and haplotype frequency at human leucocyte antigen class I/II and immunomodulatory cytokine loci in patients with myelodysplasia and acute myeloid leukaemia: in search of an autoimmune aetiology.
abstract: An autoimmune mechanism in the pathogenesis of myelodysplastic syndrome (MDS) is suggested by response to immunosuppression, with CD8+ T-lymphocytes implicated in the haematopoietic suppression. We therefore sought evidence for human leucocyte antigen (HLA) restriction and variant frequency differences in selected polymorphisms at the loci for the immunomodulatory cytokines, tumour necrosis factor alpha (TNF-alpha), lymphotoxin-alpha (LT-alpha) and interleukin 10 (IL-10) in patients with MDS and acute myeloid leukaemia (AML) compared with normal controls. DNA from 150 MDS/AML patients [24 AML, 53 refractory anaemia (RA), 25 RA with excess blasts (RAEB), four RAEB in transformation (RAEBt), 21 sideroblastic leukaemia, 22 chronic myelomonocytic leukaemia] was screened. Control data was from Scottish blood donors (HLA class I/II), healthy General Practitioner-based subjects (TNF-alpha/LT-alpha) and published values (IL-10). HLA class I/II haplotypes were determined using sequence-specific primers. Polymorphisms were assayed at TNF-alpha -308, LT-alpha +252 and IL10 -824, -597 and -1082 loci. Variant frequencies of common haplotypes at HLA class I and II, high-/low-producer TNF-alpha/LT-alpha and IL-10 loci were not different between patients and controls or within the French-American-British, International Prognostic Scoring System or cytogenetic subgroups and were not associated with altered survival for MDS/AML patients. TNF2 allele frequency was greater in the MDS/AML cohort (chi2 = 6.593, P < 0.05) but the biological significance was uncertain in the absence of an increased high-producer TNF-alpha/LT-alpha haplotype frequency. We can find no genetic influence for these polymorphisms in HLA class I/II, TNF-alpha/LT-alpha and IL-10 loci on either predisposition or disease progression in MDS/AML.
authors.affiliation: Department of Molecular and Cellular Pathology, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Gowans
authors.forename: Alan
authors.initials: A
authors.lastname: O'Sullivan
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.forename: Phillipa
authors.initials: P
authors.lastname: Roddam
authors.forename: Mike
authors.initials: M
authors.lastname: Groves
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.forename: Gareth
authors.initials: G
authors.lastname: Morgan
authors.forename: David
authors.initials: D
authors.lastname: Bowen
mesh_terms: D000208:Acute Disease; D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics / Q000276:immunology; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000276:immunology*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10