TNF

MEDIUM

Tumor necrosis factor

Chromosome: 6p21.33

Gene Overview

TNF encodes tumor necrosis factor alpha, a pro-inflammatory cytokine central to innate immunity and the acute-phase response. TNF-alpha activates NF-kB, MAPK, and apoptotic signaling cascades. The TNF-308G>A (rs1800629) promoter polymorphism increases transcriptional activity and TNF-alpha production. Elevated TNF-alpha levels are implicated in asthma, COPD, rheumatoid arthritis, inflammatory bowel disease, and cardiovascular inflammation. Gene-environment interactions with PM2.5 and tobacco smoke amplify airway inflammation in carriers of the high-expression allele.

Molecular Function

cytokine activity
pro-inflammatory signaling
NF-kB activation
apoptosis regulation

Protein class: cytokine

Regulatory Annotation

Promoter activity: TNF-308A allele increases promoter activity 2-3 fold; responsive to NF-kB, AP-1, and NFAT transcription factors.

Methylation sensitivity: Promoter methylation inversely correlated with TNF expression in airway epithelium.

eQTL tissues: lung, blood, adipose tissue, liver

Tissue Expression Context

lungTPM range: 5-40GTEx vv8

whole bloodTPM range: 10-60GTEx vv8

adipose subcutaneousTPM range: 3-20GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

asthma— G×E, strength 0.7
rheumatoid-arthritis— GWAS, strength 0.65
inflammatory-bowel-disease— GWAS, strength 0.6

Exposures

air-pollution— G×E, strength 0.75
tobacco— G×E, strength 0.7

Mechanistic Hypotheses

TNF-308A carriers produce higher TNF-alpha levels under PM2.5 exposure, amplifying NF-kB-driven airway inflammation and increasing asthma susceptibility in exposed populations.

Islam et al. EHP 2014; Li et al. Environ Toxicol Pharmacol 2017.

MEDIUM

Confidence Rating

Overall evidence confidence for this gene entry: MEDIUM

Ancestry Context

TNF-308A allele frequency: ~20% European, ~10% East Asian, ~15% African-ancestry. Effect on TNF-alpha levels consistent across ancestries.

Cross-ancestry eQTL replication: Yes

References

1.Islam T, et al. (2014). GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma. Environmental Health Perspectives. doi:10.1289/ehp.1307459
2.Berry MA, et al. (2007). The role of TNF-alpha in asthma. Current Opinion in Pharmacology. doi:10.1016/j.coph.2007.01.008