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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

Baranasic, Jurica ; Niazi, Yasmeen ; Chattopadhyay, Subhayan LU orcid ; Rumora, Lada ; Ćorak, Lorna ; Dugac, Andrea Vukić ; Jakopović, Marko ; Samaržija, Miroslav ; Försti, Asta LU and Knežević, Jelena (2023) In Acta Pharmaceutica 73(2). p.243-256
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... (More)

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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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
COPD, GWAS, immune-related genes, lung cancer, NF-κB, SNP
in
Acta Pharmaceutica
volume
73
issue
2
pages
14 pages
publisher
Croatian Pharmaceutical Society
external identifiers
  • pmid:37307368
  • scopus:85163153761
ISSN
1330-0075
DOI
10.2478/acph-2023-0019
language
English
LU publication?
yes
id
3f18e77a-2041-467b-a4fb-2e969648b063
date added to LUP
2023-09-15 12:04:04
date last changed
2024-04-19 00:54:04
@article{3f18e77a-2041-467b-a4fb-2e969648b063,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Baranasic, Jurica and Niazi, Yasmeen and Chattopadhyay, Subhayan and Rumora, Lada and Ćorak, Lorna and Dugac, Andrea Vukić and Jakopović, Marko and Samaržija, Miroslav and Försti, Asta and Knežević, Jelena}},
  issn         = {{1330-0075}},
  keywords     = {{COPD; GWAS; immune-related genes; lung cancer; NF-κB; SNP}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{243--256}},
  publisher    = {{Croatian Pharmaceutical Society}},
  series       = {{Acta Pharmaceutica}},
  title        = {{Germline variants of the genes involved in NF-kB activation are associated with the risk of COPD and lung cancer development}},
  url          = {{http://dx.doi.org/10.2478/acph-2023-0019}},
  doi          = {{10.2478/acph-2023-0019}},
  volume       = {{73}},
  year         = {{2023}},
}