| 1. |
- Baranasic, Jurica, et al.
(författare)
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Germline variants of the genes involved in NF-kB activation are associated with the risk of COPD and lung cancer development
- 2023
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Ingår i: Acta Pharmaceutica. - 1330-0075. ; 73:2, s. 243-256
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are closely related diseases associated with smoking history and dysregulated immune response. However, not all smokers develop the disease, indicating that genetic susceptibility could be important. Therefore, the aim of this study was to search for the potential overlapping genetic biomarkers, with a focus on single nucleotide polymorphisms (SNPs) located in the regulatory regions of immune-related genes. Additionally, the aim was to see if an identified SNP has potentially an effect on proinflamma-tory cytokine concentration in the serum of COPD patients. We extracted summary data of variants in 1511 immune-related genes from COPD and LC genome-wide association studies (GWAS) from the UK Biobank. The LC data had 203 cases, patients diagnosed with LC, and 360 938 controls, while COPD data had 1 897 cases and 359 297 controls. Assuming 1 association/gene, SNPs with a p-value < 3.3 × 10-5 were considered statistically significantly associated with the disease. We identified seven SNPs located in different genes (BAG6, BTNL2, TNF, HCP5, MICB, NCR3, ABCF1, TCF7L1) to be associated with the COPD risk and two with the LC risk (HLA-C, HLA-B), with statistical significance. We also identified two SNPs located in the IL2RA gene associated with LC (rs2386841; p = 1.86 × 10-4) and COPD (rs11256442; p = 9.79 × 10-3) but with lower significance. Functional studies conducted on COPD patients showed that RNA expression of IL2RA, IFNγand related proinflammatory cytokines in blood serum did not correlate with a specific genotype. Although results presented in this study do not fully support our hypothesis, it is worth to mention that the identified genes/SNPs that were associated with either COPD or LC risk, all were involved in the activation of the NF-κB transcription factor which is closely related to the regulation of the inflammatory response, a condition associated with both pathologies.
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| 2. |
- Klimosch, Sascha N., et al.
(författare)
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Functional TLR5 Genetic Variants Affect Human Colorectal Cancer Survival
- 2013
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Ingår i: Cancer Research. - 1538-7445. ; 73:24, s. 7232-7242
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1 beta mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development. (C)2013 AACR.
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