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

• Published in: British journal of haematology Vol. 117; no. 3; pp. 541 - 545
• Main Authors: Gowans, Duncan, O'Sullivan, Alan, Rollinson, Sara, Roddam, Phillipa, Groves, Mike, Fegan, Chris, Morgan, Gareth, Bowen, David
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.06.2002; Blackwell
• Subjects: Acute Disease; Alleles; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Biological and medical sciences; Cytokines - genetics; Genotype; haplotype; Haplotypes; Hematologic and hematopoietic diseases; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class II - genetics; Histocompatibility Testing; HLA; HLA Antigens - genetics; Humans; IL‐10; Interleukin-10 - genetics; Leukemia, Myeloid - genetics; Leukemia, Myeloid - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; myelodysplastic syndrome; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - immunology; Survival Rate; TNF; Tumor Necrosis Factor-alpha - genetics; Autoimmunity; Human; HLA-System; Pathogenesis; Acute; Major histocompatibility system; Genetic variant; Cytokine; Class II histocompatibility antigen; Malignant hemopathy; Genetic determinism; Myelodysplastic syndrome; Interleukin 10; Genetics; Haplotype; Class I histocompatibility antigen; Tumor necrosis factor α; Acute myelocytic leukemia
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.2002.03452.x

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 α (TNF‐α), lymphotoxin‐α (LT‐α) 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‐α/LT‐α) and published values (IL‐10). HLA class I/II haplotypes were determined using sequence‐specific primers. Polymorphisms were assayed at TNF‐α−308, LT‐α +252 and IL10 −824, −597 and −1082 loci. Variant frequencies of common haplotypes at HLA class I and II, high‐/low‐producer TNF‐α/LT‐α 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 (χ2 = 6·593, P < 0·05) but the biological significance was uncertain in the absence of an increased high‐producer TNF‐α/LT‐α haplotype frequency. We can find no genetic influence for these polymorphisms in HLA class I/II, TNF‐α/LT‐α and IL‐10 loci on either predisposition or disease progression in MDS/AML.