rs1800629 — TNF -308 G>A

Promoter variant increasing TNF-alpha production 2-3 fold, associated with autoimmune diseases and anti-TNF drug response

Strong Risk Factor

Details

Gene: TNF
Chromosome: 6
Risk allele: A
Consequence: Regulatory
Inheritance: Codominant
Clinical: Risk Factor
Evidence: Strong
Chip coverage: v3 v4 v5

Population Frequency

24%

74%

Ancestry Frequencies

european

16%

latino

15%

african

14%

south_asian

12%

east_asian

External

SNPedia ClinVar dbSNP

TNF-308: The Inflammation Amplifier

The TNF gene encodes tumor necrosis factor-alpha¹¹ tumor necrosis factor-alpha
a master regulator of inflammation and immune response, produced by macrophages, T cells, and other immune cells. This -308 G>A variant sits in the promoter region²² promoter region
the DNA sequence that controls how much TNF-alpha gets made of the gene on chromosome 6p21.3, within the major histocompatibility complex. The A allele disrupts transcription factor binding sites and increases TNF-alpha production 2-3 fold compared to the G allele when immune cells are stimulated.

The Mechanism

This is a regulatory variant that affects gene transcription³³ affects gene transcription
how much protein gets made from the gene. The -308 position is 308 base pairs upstream of where the TNF gene starts being copied into RNA. The A allele alters binding sites for transcription factors like SP1, leading to enhanced transcriptional activity in immune cells. When your immune system encounters a threat, carriers of the A allele produce substantially more TNF-alpha than GG carriers, amplifying the inflammatory response.

The Evidence

A meta-analysis of 1,774 controls and 1,147 celiac disease cases found the A allele confers a 2-fold increased risk (OR 2.051) , with

AA homozygotes showing 6.6-fold increased risk (OR 6.626) .

The A allele leads to 2-3 fold higher TNF-alpha transcription upon stimulation with bacterial lipopolysaccharide , and carriers show significantly higher serum TNF-alpha levels .

The variant also predicts response to anti-TNF biologic drugs⁴⁴ anti-TNF biologic drugs
medications like infliximab and etanercept that block TNF-alpha used to treat rheumatoid arthritis and inflammatory bowel disease.

RA patients carrying the GG genotype are better responders to infliximab, while the A allele significantly decreases response .

The same pattern holds for etanercept—GG shows better response than AA or AG .

Associations have been reported with multiple autoimmune conditions.

In rheumatoid arthritis patients, A allele carriers show higher risk of cardiovascular events (HR 1.72), particularly in those also carrying the rheumatoid shared epitope . Studies link the variant to increased risk of vitiligo, preeclampsia in Asian and Caucasian populations, and aggressive periodontitis.

Practical Implications

If you have autoimmune disease, particularly rheumatoid arthritis or inflammatory bowel disease, your -308 genotype may influence how well you respond to anti-TNF biologic medications. GG carriers tend to respond better to drugs like infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). If you're an A allele carrier who doesn't respond well to one anti-TNF drug, switching to a different mechanism of action (like IL-6 inhibitors or JAK inhibitors) may be more effective than trying another anti-TNF.

For those with one or two A alleles, managing chronic inflammation through lifestyle becomes particularly important. The A allele doesn't cause inflammation by itself—it amplifies your body's inflammatory response when triggered. This means greater attention to anti-inflammatory diet patterns, adequate sleep, stress management, and avoiding known inflammatory triggers.

Interactions

The TNF-308 variant sits within a cluster of related TNF polymorphisms including rs361525⁵⁵ rs361525
TNF-238 G>A, another promoter variant and rs1799724⁶⁶ rs1799724
TNF-857 C>T. These variants are in linkage disequilibrium, meaning they're often inherited together. Compound effects with other inflammatory pathway genes (IL-6, IL-10, IL-1) have been documented, particularly for predicting anti-TNF drug response.

Genotype Interpretations

What each possible genotype means for this variant:

GG “Normal TNF Production” Normal

Standard inflammatory response and good anti-TNF drug response

You have two copies of the common G allele. Your cells produce normal amounts of TNF-alpha when your immune system is activated. About 74% of people carry this genotype. If you develop an autoimmune condition requiring anti-TNF biologic therapy, research suggests you're likely to respond well to these medications.

AG “Elevated TNF Producer” Intermediate Caution

Moderately increased TNF-alpha production and intermediate drug response

You have one copy of the A allele and one G allele. Your immune cells produce moderately elevated levels of TNF-alpha when stimulated—roughly 1.5-2 fold higher than GG carriers. About 24% of people share this genotype. This creates a mildly amplified inflammatory response and may influence your response to anti-TNF medications if you need them for autoimmune disease.

AA “High TNF Producer” High Warning

Significantly elevated TNF-alpha production and reduced anti-TNF drug response

The double A variant creates a "high producer" phenotype. When your immune system encounters triggers—whether infection, stress, poor diet, or in the context of autoimmune disease—you generate much more TNF-alpha than most people. This isn't necessarily problematic if you don't have autoimmune disease, but it means your body's inflammatory "volume knob" is turned up higher. The variant is particularly relevant if you develop rheumatoid arthritis, Crohn's disease, or other conditions treated with anti-TNF biologics, as the same mechanism that creates high TNF production appears to confer resistance to these drugs.