rs1799724 — TNF -857C>T

TNF promoter variant that disrupts an OCT-1 binding site, altering TNF-alpha transcription independently of the -308 variant; the T allele is associated with Crohn's disease susceptibility in Asian populations, psoriasis, and modified response to anti-TNF biologics

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TNF -857C>T: A Distinct Inflammatory Control Point

The TNF gene on chromosome 6p21.3 encodes tumor necrosis factor-alpha11 tumor necrosis factor-alpha
a master cytokine controlling inflammation, immune cell activation, and apoptosis. The rs1799724 variant sits 857 base pairs upstream of the TNF transcription start site, within the gene's promoter — a regulatory region that controls how much TNF-alpha your immune cells produce. Unlike the well-studied -308 variant (rs1800629), the -857C>T polymorphism works through a distinct molecular mechanism and shows population-specific disease associations.

The Mechanism

The -857 position overlaps an OCT-1 binding site22 OCT-1 binding site
a binding site for octamer transcription factor-1, a protein that binds to DNA and regulates nearby gene expression. The T allele disrupts this binding site, altering the transcriptional regulation of TNF-alpha. The TNF gene is on the forward (plus) strand, so the C>T notation in papers corresponds directly to plus-strand alleles as reported in genome files.

The Evidence

The clearest disease association for the -857 T allele is in Asian populations with Crohn's disease33 Crohn's disease
a chronic inflammatory bowel disease affecting the gastrointestinal tract. A meta-analysis found that Asians carrying the T allele had a 54% increased risk of Crohn's disease compared to CC carriers (OR 1.54, 95% CI 1.19–1.99). This ethnic specificity is notable — studies in European and Middle Eastern populations have not consistently replicated the IBD association, underscoring the importance of population context in interpreting this variant.

For psoriasis, a 2023 systematic review and meta-analysis44 2023 systematic review and meta-analysis
Sadafi et al., Heliyon found robust associations across five genetic models: the T allele conferred OR 1.57 in allelic comparison, and TT homozygotes showed OR 1.98 for psoriasis risk. This association was confirmed by trial sequential analysis, suggesting sufficient evidence for a genuine effect. The -857 variant is also among polymorphisms associated with psoriatic arthritis in a meta-analysis of 14 studies.

A clinically important finding concerns response to anti-TNF biologic drugs55 anti-TNF biologic drugs
medications like infliximab, adalimumab, and etanercept that block TNF-alpha protein. A meta-analysis found that the common C allele — not the risk T allele — is associated with better response to TNF blockers (OR 1.78, 95% CI 1.13–2.80). Carriers of the T allele may therefore show reduced efficacy from anti-TNF biologics in conditions like Crohn's disease and spondyloarthropathy. A recent meta-analysis also links the T allele to increased type 1 diabetes susceptibility.

Practical Actions

For T allele carriers with active or suspected inflammatory bowel disease — particularly those of East Asian ancestry — this variant provides one more reason to pursue thorough gastroenterological evaluation. The -857 T allele adds biologically independent risk information beyond the more commonly tested -308 variant.

For T allele carriers with psoriasis or psoriatic arthritis, awareness of this genetic background may be relevant when discussing biologic therapy choices: if anti-TNF drugs are being considered, the -857 T allele predicts a somewhat less favorable response compared to C allele carriers. Switching to IL-17 or IL-23 inhibitors may be a better initial strategy.

Interactions

The -857 variant sits within a cluster of TNF promoter polymorphisms, including rs180062966 rs1800629
TNF -308 G>A, the most studied TNF promoter variant, rs180063077 rs1800630
TNF -863 C>A, and rs36152588 rs361525
TNF -238 G>A. The combined effect of multiple TNF promoter variants on biologic drug response has been studied in Crohn's disease and psoriasis, and T allele carriers at -857 may compound the reduced anti-TNF response seen with A allele carriers at -308.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal TNF Regulation Normal

Common genotype with standard TNF promoter function

You have two copies of the common C allele at the TNF -857 position. This genotype preserves normal OCT-1 binding at the TNF promoter and is associated with standard TNF-alpha regulation. About 82% of people carry this genotype globally, though frequencies vary by ancestry. If you have autoimmune disease requiring biologic therapy, CC carriers tend to respond better to anti-TNF drugs than T allele carriers.

CT Elevated Inflammatory Risk Intermediate

One copy of the T allele — moderately elevated TNF regulatory risk

The -857 CT genotype carries one copy of the T allele, which alters OCT-1 transcription factor binding at the TNF promoter. This variant operates via a distinct mechanism from the more commonly tested -308 variant (rs1800629), meaning -857 provides independent information about TNF regulation. Population stratified meta-analyses show consistent psoriasis risk associations for heterozygotes (OR ~1.61), while IBD risk appears stronger in East Asian than European populations. Anti-TNF drug response meta-analyses suggest the C allele (not T) predicts better response; heterozygotes occupy an intermediate position.

TT Homozygous Inflammatory Risk High Risk

Two copies of the T allele — highest TNF -857 inflammatory risk

TT homozygosity for TNF -857 produces the maximal disruption of OCT-1 binding at this promoter site, creating the highest allele dose of T-allele-mediated TNF dysregulation. The psoriasis meta-analysis found homozygous recessive OR of 1.79 under the recessive model, and the dominant + recessive data converge on TT as the highest-risk group. The Crohn's disease risk in Asian populations (OR 1.54 from the Han et al. meta-analysis) is also expected to be higher in TT versus CT carriers. As with CT carriers, anti-TNF drug response data favor C allele carriers, making TT homozygotes less likely to achieve optimal outcomes from first-line anti-TNF biologics.