In silico analysis of the impact of toxic metals on COVID-19 complications: molecular insights

Toxic metals	Total number of genes	Genes associated with COVID-19
Arsenic (As)	4997	ATP11A, BCL11A, CCL2, CCL3, CCR2, CRP, CXCL8, ICAM5, IFNAR2, IL10, IL10RB, IL1B, IL2, IL2RA, IL6, IL7, LZTFL1, MUC1, OAS1, TNF
Cadmium (Cd)	5281	AGT, CCL2, CCR2, CD209, CRP, CXCL8, F8, HCK, IL10, IL1B, IL2, IL6, IL7, MUC1, OAS1, SELE, TNF, UGCG
Lead (Pb)	3278	AGT, BSG, CCL2, CCL3, CD209, CRP, CXCL10, CXCL8, ICAM5, IL10, IL1B, IL6, TNF
Mercury (Hg)	635	CCL3, CCR2, CRP, CXCL8, IL10, IL1B, IL2, IL6, TNF, UGCG
Nickel (Ni)	7665	ACE2, AGT, BCL11A, BTK, CCL2, CCL3, CCR2, CD209, CRP, CXCL10, CXCL8, FUT2, HCK, IFNAR2, IL10, IL10RB, IL1B, IL2, IL2RA, IL6, IL7, OAS1, PLSCR1, SELE, TMPRSS2, TMPRSS4, TNF
Chromium (Cr)	2353	AGT, CXCL8, IL10, IL1B, IL6, TNF, UGCG
As+Cd+Pb+Hg+Ni+Cr	5	*CXCL8, IL10, IL1B, IL6, TNF*

Table 2

Effects of As, Cd, Pb, Hg, Ni, and Cr on common genes

Toxic metals	Interactions	*CXCL8*	*IL10*	*IL1B*	*IL6*	*TNF*
As	Expression of mRNA	N/A	↓	↓↑	↑	↓
As	Protein expression	↑	↑	↓↑	↑	↓↑
Cd	Expression of mRNA	↑	↓	↓↑	↓↑	↓↑
Cd	Protein expression	↑	↑	↑	↑	↑
Pb	Expression of mRNA	↑	N/A	↑	N/A	↑
Pb	Protein expression	↑	↓↑	↑	↑	↑
Hg	Expression of mRNA	N/A	↑	↑	N/A	↑
Hg	Protein expression	↑	N/A	↑	↑	↑
Ni	Expression of mRNA	↑	↑	↑	↑	↑
Ni	Protein expression	↑	N/A	↑	↑	↑
Cr	Expression of mRNA	↑	N/A	N/A	N/A	↑
Cr	Protein expression	N/A	N/A	N/A	↓	↑

[i] ↑ – upregulation; ↓ – downregulation; ↑↓ – upregulation and downregulation. N/A – no data available in CTD; IL1B – interleukin 1b; IL6 – interleukin 6; IL10 – interleukin 10; CXCL8 – interleukin 8; TNF – tumour necrosis factor

Network of five genes/proteins associated with the development of COVID-19 and affected by As, Cd, Pb, Hg, Ni, and Cr and their relationship with 20 genes/proteins, identified by the GeneMANIA prediction tool (*https://genemania.org*). Legend: pink lines – physical interactions; purple lines – co-expression; orange lines – server-predicted interactions; blue lines – co-localisation; green lines – genetic interactions; light blue lines – shared pathway; gray-yellow lines – shared protein domains

Networks of five genes/proteins associated with the development of COVID-19 and the 20 related genes for each toxic metal separately. Legend: pink lines – physical interactions; purple lines – co-expression; orange lines – server-predicted interactions; blue lines – co-localisation; green lines – genetic interactions; light blue lines – shared pathway; gray-yellow lines – shared protein domains

Table 3

Correlation of the 25 identified genes (five common and 20 related) with biological processes, molecular functions, pathways, and diseases associated with COVID-19 complications

Category	Name	ID	p-value	Genes involved*
Molecular function	cytokine binding	GO:0019955	1.341E-17	11
	cytokine receptor binding	GO:0005126	2.170E-17	13
	cytokine activity	GO:0005125	3.580E-15	11
	signalling receptor binding	GO:0005102	1.187E-11	16
	receptor ligand activity	GO:0048018	1.952E-11	11
Biological process	inflammatory response	GO:0006954	4.830E-28	23
	cytokine-mediated signalling pathway	GO:0019221	1.992E-25	19
	cellular response to cytokine stimulus	GO:0071345	1.277E-20	19
	response to cytokine	GO:0034097	9.706E-20	19
	leukocyte migration	GO:0050900	8.016E-19	15
Pathway	KEGG cytokine receptor interaction	M9809	1.039E-30	20
	reactome interleukin 10 signalling	M27605	6.459E-22	11
	reactome signalling by interleukins	M874	4.294E-18	16
	WP SARSCOV2 innate immunity evasion and cell-specific immune response	M40067	9.207E-18	10
	WP overview of proinflammatory and profibrotic mediators	M42533	1.091E-16	11
Disease	susceptibility to HIV infection	609423	6.577E-6	3
	malaria, susceptibility to	cv:C1836230	6.577E-6	3
	white blood cell count quantitative trait locus 1	611162	5.893E-4	2
	WHIM syndrome 2	cv:C1970028	5.893E-4	2
	Graft-versus-host disease, susceptibility to	611862	2.333E-3	1

* Number of genes involved in each category. KEGG – Kyoto Encyclopedia of Genes and Genomes; WHIM – warts, hypogammaglobulinaemia, infections, and myelokathexis syndrome type 2; WP – WikiPathways

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DOI: https://doi.org/10.2478/aiht-2024-75-3819 | Journal eISSN: 1848-6312 (formerly 0004-1254) | Journal ISSN: 0004-1254

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Language: English, Croatian

Page range: 102 - 109

Submitted on: Jan 1, 2024

Accepted on: May 1, 2024

Published on: Jun 29, 2024

Published by: Institute for Medical Research and Occupational Health

In partnership with: Paradigm Publishing Services

Keywords:

Comparative Toxicogenomic Database,

cytokines,

genes,

physical interactions,

SARS-CoV-2

Related subjects:

Medicine,

Basic medical science,

Basic medical science, other

© 2024 Jovana Živanović, Katarina Baralić, Katarina Živančević, Dragica Božić, Đurđica Marić, Evica Antonijević Miljaković, Aleksandra Buha Đorđević, Marijana Ćurčić, Zorica Bulat, Biljana Antonijević, Danijela Đukić-Ćosić, published by Institute for Medical Research and Occupational Health
This work is licensed under the Creative Commons Attribution 4.0 License.

Volume 75 (2024): Issue 2 (June 2024)

In silico analysis of the impact of toxic metals on COVID-19 complications: molecular insights

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