Single nucleotide polymorphisms (SNPs) in the promoter regions of cytokine genes are associated with differential levels of cytokine expression. We hypothesized that these SNPs might influence breast tumour development and progression by affecting the efficiency of the antitumour immune response and/or pathways of angiogenesis. A total of 144 female breast cancer patients and 263 cancer-free population controls were genotyped for the interleukin (IL)-1beta-511 (T/C), IL-6 -174 (G/C), tumour necrosis factor (TNF)-alpha-308 (A/G), IL-10 -1082 (A/G), IL-8 -251 (A/T) and vascular endothelial growth factor (VEGF) -1154 (A/G) SNPs, using amplification refractory mutation system polymerase chain reaction (ARMS-PCR) and TaqMan (Applied Biosystems, Foster City, CA, USA) 5' nuclease assays for allelic discrimination. No significant associations were seen. Patient-control comparisons revealed a non-significant trend for association between the TNF-alpha-308 GG genotype and breast cancer compared to controls (79.7 vs. 68.2%, P = 0.03, Pc = 0.54). Stratification of the patient group according to the Nottingham Prognostic Index and individual prognostic factors revealed trends for association between IL-6 -174 GC and IL-8 -251 AA genotypes and markers of poor prognosis (P = 0.04, Pc = 0.72 and P = 0.02, Pc = 0.36, respectively). There were also trends for associations between VEGF -1154 AG and IL-1beta-511 TC genotypes and markers of good prognosis (P = 0.02, Pc = 0.36 and P = 0.05, Pc = 0.90, respectively). These results suggest that the role of cytokine promoter SNPs in both susceptibility to and prognosis in breast cancer requires further investigation in a larger study.
HLA-B27 heavy chain-dimerization is a complex process and these findings provide an insight into HLA-B27 misfolding and a potential contribution to inflammatory disease development.
Objective. The class I major histocompatibility complex (MHC) molecule HLA-B27 exhibits a strong association with the autoimmune inflammatory arthritis disorder ankylosing spondylitis (AS) and with other related spondylarthropathies. In the absence of both a defined autoimmune response and a target autoantigen(s), the propensity of HLA-B27 to misfold has been hypothesized to be a major parameter in disease pathogenesis. We undertook this study to test the hypothesis that HLA-B27 misfolding is due to exposure of cysteine residues within the heavy chain to the oxidizing environment of the endoplasmic reticulum.Methods. A rapid acidification and alkylation modification method was used to examine cysteine residue exposure and accessibility within AS-associated and non-AS-associated HLA-B27 subtypes.Results. This novel approach to probing in vivo class I MHC structure revealed that the HLA-B27 heavy chain adopts conformations not previously described. Furthermore, amino acid residues specific to subtypes HLA-B*2706, B*2709, and B*2704 can have an impact on these novel conformations and on cysteine residue exposure.Conclusion. HLA-B27 can adopt novel conformations, resulting in differential accessibility of cysteine residues, which can explain the propensity to misfold. Cysteine exposure in the HLA-B27 heavy chain is also affected by residues within the 114 and 116 regions, thereby providing a potential biochemical basis for the association of HLA-B27 subtypes with AS.
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