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

Summary. 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.

DNA polymorphisms and response to treatment in patients with chronic hepatitis C: Results from the HALT-C trial

“…Although neither the IL10À1082 nor the IL10À592 promoter polymorphism alone predicted response to treatment, the IL10 ACC/ACC diplotype was associated with SVR and this association was relatively strong, especially after adjustment for other predictors of SVR. We also note that the frequency of ACC/ACC diplotype among the HALT-C population (5.8%) was lower than that observed in the general adult population by Trompet (7.3%), Gowans (7.8%) and Klein (10%) [28][29][30] suggesting that subjects with this diplotype were underrepresented in the HALT-C cohort, perhaps Table 1 Selected demographic and clinical features of subjects participating in the Lead-in phase of the HALT-C trial, the genetics ancillary study, and in the current report…”

Polymorphisms of IL‐10 affect the severity and prognosis of myelodysplastic syndrome

“…Although Gowans et al . showed no relationship between IL‐10 ‐1082, ‐819, and ‐592 polymorphisms and disease progression in MDS, the present study showed that the IL‐10 high producer type (GCC/ACC or ACC/ACC haplotype, ‐819CC and ‐592CC genotype) was significantly associated with poor survival and leukemia progression. The frequency of polymorphism of the IL‐10 promoter in different races may affect the different influence.…”

Associação entre HLA e leucemia em uma população brasileira de etnia mista

“…Além disso, vários outros trabalhos de associação entre o sistema HLA e leucemias foram realizados por autores em vários países, com resultados variáveis [14][15][16][17][18] .…”