Interleukin 6 gene polymorphism is associated with protein serum level and disease activity in Polish patients with rheumatoid arthritis.

Interleukin 6 (IL-6) is a pro-inflammatory cytokine involved in the development of rheumatoid arthritis (RA). The present study aimed to determine the possible association of the IL6 (rs1800795, G > C) polymorphism with RA susceptibility, disease progression and protein serum levels. Distribution of IL6 alleles and genotypes was similar in RA patients and controls. As expected, patients before induction of anti-tumour necrosis factor agents had significantly higher IL-6 levels as compared with controls (P = 0.002). The CC homozygous patients were characterised with the highest average concentrations of this pro-inflammatory cytokine before treatment (P = 0.028), and they also more frequently presented with more active disease (P = 0.048). These results imply that the IL6 rs1800795 CC homozygosity may play a rather unfavourable role in RA.

Variations in genes involved in regulation of the nuclear factor - κB pathway and the risk of acute myeloid leukaemia.

Genes involved in regulation of the nuclear factor - kappa B (NF-κB) pathway are suggested to play a role in the pathogenesis of acute myeloid leukaemia (AML). The present study aimed to assess the association between the NF-κB1, TRAF3 and TLRs genes single nucleotide polymorphisms (SNPs) and disease susceptibility as well as progression in patients with AML. For this purpose 62 patients and 126 healthy individuals were genotyped for NF-κB1 (rs28362491), TRAF3 (rs11160707; rs12147254), TLR2 (rs201786064), TLR4 (rs4986790; rs4986791) and TLR9 (rs5743836; rs187084) alleles. Three SNPs were found to be associated with the risk for the AML development. The TRAF3 (rs12147254) AA homozygosity (RR = 2.770, P = 0.0392), TLR9 (rs5743836) C wild-type allele (RR = 2.542, P = 0.0096) as well as TLR9 (rs187084) T allele (RR = 13.396, P < 0.0001) and its homozygosity (RR = 11.805, P < 0.0001) were more frequent among patients with AML than healthy individuals. The associations of the rs187084 SNP were significant for both sexes. Moreover, patients who relapsed were more frequently characterized with the presence of the rs187084 TLR9 TT genotype (P = 0.045) or the rs12147254 TRAF3 A variant (P = 0.066). In conclusion, polymorphisms within the TLR9 and TRAF3 genes are associated with predisposition to AML and may affect the progression of the disease in the Polish population.

Role of the functional MNS16A VNTR-243 variant of the human telomerase reverse transcriptase gene in progression and response to therapy of patients with non-Hodgkin's B-cell lymphomas.

MNS16A is a functional polymorphic tandem repeat within the human telomerase reverse transcriptase (hTERT) gene. To investigate whether any of the MNS16A repeats represents a genetic risk factor for NHL susceptibility, progression of or response to therapy in 75 patients with non-Hodgkin's lymphomas (NHLs) and 126 healthy individuals were genotyped using the PCR-VNTR technique. A slightly higher frequency of the MNS16A VNTR-243 variant was detected among patients who did not respond to treatment (NR) as compared to patients with complete or partial remission (0.83 vs. 0.51, P = 0.055). NR patients more frequently developed aggressive than indolent type of the disease (0.92 vs. 0.41, P = 0.001). The VNTR-243 allele was more frequently detected among patients with an intermediate-high/high International Prognostic Index (IPI 3-4) score (P = 0.063), especially in patients with advanced age and IPI 3-4 (P = 0.040). In multivariate analysis, higher IPI 3-4 score (OR = 11.364, P = 0.051) and aggressive type of the disease (OR = 18.182, P = 0.012) were found to be independent genetic markers associated with nonresponse to treatment. Presence of the MNS16A VNTR-243 variant also strongly tended to affect the risk of a less favourable response to therapy and was more frequently present among nonresponders (OR = 5.848, P = 0.059). Genetic variation within the hTERT gene may affect the progression and treatment of lymphoproliferative disorders.

Chimerism in children with primary immunodeficiencies is influenced by number of activating killer cell immunoglobulin-like receptor genes in the donor and/or killer cell immunoglobulin-like receptor ligand mismatch.

BACKGROUND: Stem cell transplantation (SCT) is a curative treatment for children with primary immunodeficiencies. METHODS: The present retrospective analysis describes the long-term outcomes at a median follow-up of 9 years of 29 patients with immunodeficiency after SCT; 5 sibling and 24 alternative donor transplantations. T-cell engraftment emphazed on thymic dependent signal-joint T-cell receptor excision circles (sjTREC) generation and donor chimerism in relation to killer cell immunoglobulin-like receptor genes and their ligands. RESULTS: All children except two were reconstituted successfully from grafted material, including 9 and 18 cases of mixed chimerism (MC) and complete chimerism (CC), respectively. Univariate analyses showed that the number of activating KIR genes or HLA-C1/C2 ligand mismatches (P = .048) and possibly transplantation from an alternative donor (P = .054) facilitated CC development. Multivariate analysis showed that the presence of donor KIR haplotype B or incompatibility within C1/C2 ligands (relative risk, 6.1; 95% confidence interval, 1.08-34.69; P = .025) were significantly associated with the development of CC. CONCLUSIONS: These results suggested that the donor-activating KIR gene repertoire affected successful engraftment.

Association with the presence of naive T cells in chronic myeloid leukemia patients after allogeneic human stem cell transplantation and the lower incidence of chronic graft-versus host disease and relapse.

INTRODUCTION: Allotransplantation in chronic myeloid leukemia (CML) patients offers long-lasting remissions, which largely depend on immunologic surveillance of alloreactivity. Alloreactivity in CML patients has a durable potential. However a large proportion of relapsing patients, who have to undergo donor lymphocyte treatment is still abundant. METHODS: We studied a group of 31 CML patients post allogeneic transplantation for their level of T-cell receptor excision circles (TREC) and proportion of naive and memory/effector T cells in the peripheral blood (PB). TREC numbers were determined by quantitative PCR (qPCR) and T-cell subsets CD4(+)CD27(+)CD45RO(-), CD4(+)CD27(-)CD24RO(+), CD4(+)CCR7(+), and CD4(+)CCR7(-) by flow cytometry. Patients were analyzed for posttransplant chimerism, type of bcr-abl transcripts, and number of TREC in association with the presence of chronic graft-versus-host disease (cGVHD) and relapse. CML patients with TREC+ in PB had a higher proportion of CD4(+)CD27(+)CD45RO(-) cells (3.54 vs 2.45%; P = .105) and CD4(+)CCR7(+) cells (4.85 vs 2.67%; P = .007), and a lower proportion of CD4(+)CD27(-)CD45RO(+) cells (5.55 vs 9.09%; P = .037). The incidence of cGvHD was reduced among TREC+ CML patients (3/14 vs 11/17; P = .006). RESULTS: The 5 out of 31 CML patients who relapsed were characterized by the presence of b2a2, b3/a2 or both type of transcripts, a lack of TREC in the blood, and a lower proportion of naïve and effector/memory T cells. No association was observed between any of HLA specificities, type of bcr-abl transcripts and incidence of relapse. CONCLUSION: The presence of TREC is affected by chronic GvHD; TREC negativity may constitute a risk of mixed chimerism and relapse.

Lack of IFN-gamma 2/2 homozygous genotype independently of recipient age and intensity of conditioning regimen influences the risk of aGVHD manifestation after HLA-matched sibling haematopoietic stem cell transplantation.

A total of 110 patients (71 adults and 39 children) who received allogeneic haematopoietic stem cell transplantation from HLA-matched sibling donors were studied for the incidence of acute graft-versus-host disease (aGvHD) in relation to IFN-gamma gene microsatellite polymorphism. A strong tendency was observed towards the lower incidence of grades II-IV aGvHD in patients having an IFN-gamma 2/2 genotype as compared to the recipients with other IFN-gamma genotypes (0.12 vs 0.33, P=0.06). This relationship was independent of the intensity of conditioning regimen and diagnosis. IFN-gamma polymorphic features, together with other clinical and biological factors (patient's age, donor-recipient gender, diagnosis, conditioning regimen, transplant material and GvHD prophylaxis), were subjected to multivariate analysis for aGvHD manifestation in order to exclude indirect association of the IFN-gamma 2/2 genotype. In multivariate analysis, myeloablative therapy (OR=11.462, P=0.013), recipient age (OR=4.896, P=0.009) and lack of IFN-gamma 2/2 genotype (OR=4.311, P=0.048) were found to significantly contribute to the development of grade II-IV aGvHD, while type of GvHD prophylaxis showed less-strong influence (OR=2.963, P=0.066). Thus, it appeared that the IFN-gamma 2/2 genotype constituted an independent and protective factor associated with a decreased risk of grade II-IV aGvHD. However, this genotype was not found to be associated with the risk of cGvHD or survival.