The TNF G-238A polymorphism (rs361525) is another important variant in the tumor necrosis factor alpha promoter region, located 238 base pairs upstream of the transcription start site. While less studied than G-308A, this variant has distinct associations with inflammatory conditions, particularly psoriasis and other skin conditions. Understanding both TNF promoter variants gives a more complete picture of your inflammatory genetics.
Understanding TNF G-238A
This variant is in the promoter region, affecting gene regulation:
- Location: 238 base pairs upstream of TNF gene start
- G allele: Reference allele - standard promoter activity
- A allele: Variant allele - altered promoter activity
How It Differs from G-308A
The two TNF promoter variants have different effects:
| Feature | G-308A (rs1800629) | G-238A (rs361525) |
|---|---|---|
| A allele effect | Increases TNF production | May decrease TNF in some contexts |
| Frequency | A allele ~15-20% | A allele ~5-10% |
| Primary associations | Autoimmune diseases | Psoriasis, certain infections |
Understanding Your Genotype
- G/G: Standard TNF regulation at this position (most common)
- G/A: Heterozygous - altered regulation
- A/A: Homozygous variant (rare)
Psoriasis Connection
G-238A has one of the strongest genetic associations with psoriasis:
Risk and Severity
- A allele associated with significantly increased psoriasis risk
- Some studies show 2-3x increased odds of developing psoriasis
- May affect age of onset
- Could influence disease severity and extent
Mechanism
- TNF-alpha is central to psoriasis pathophysiology
- Drives keratinocyte proliferation
- Promotes inflammatory cell recruitment to skin
- Stimulates other pro-inflammatory cytokines
Treatment Implications
- Anti-TNF biologics (adalimumab, infliximab, etanercept) highly effective for psoriasis
- Genotype might predict treatment response
- A allele carriers may be particularly good responders
- Personalized medicine applications being researched
Other Skin Conditions
Psoriatic Arthritis
- Often accompanies skin psoriasis
- G-238A associated with joint involvement
- May predict which psoriasis patients develop arthritis
Other Inflammatory Skin Diseases
- Eczema: Some associations reported
- Hidradenitis suppurativa: TNF-alpha implicated
- Pyoderma gangrenosum: TNF inhibitors used as treatment
Skin Inflammation Response
- May affect how skin responds to irritants
- Could influence contact dermatitis severity
- Wound healing inflammatory phase affected
Immune System Effects
Infection Response
- TNF-alpha critical for pathogen defense
- Variant may affect susceptibility to certain infections
- Tuberculosis associations studied
- Viral infection responses may vary
Autoimmune Considerations
- Different pattern than G-308A
- Some protective effects reported for certain conditions
- Context-dependent effects on inflammation
Vaccination Response
- TNF-alpha involved in vaccine immune response
- Genotype might affect antibody development
- Research ongoing in this area
Cancer Associations
Research Findings
- TNF-alpha has complex roles in cancer
- Can promote or inhibit tumor growth depending on context
- G-238A studied in various cancer types
- Some associations with gastric, breast, and other cancers
Interpretation Challenges
- Results vary across populations and cancer types
- Interaction with other genetic and environmental factors
- Not currently used for clinical cancer risk assessment
Interaction with G-308A
The two TNF promoter variants should be considered together:
Haplotype Effects
- Variants inherited together form haplotypes
- Specific combinations may have distinct effects
- G-308A and G-238A are in linkage disequilibrium
Combined Risk Assessment
- Having risk alleles at both positions may compound effects
- Or in some cases, one may modify the other
- Complete picture requires analyzing both
Managing Inflammation
Diet and Nutrition
- Anti-inflammatory foods: Fatty fish, olive oil, leafy greens, berries
- Omega-3 fatty acids: Reduce TNF-alpha production
- Turmeric/curcumin: Potent TNF inhibitor
- Avoid: Processed foods, refined sugars, trans fats
Lifestyle Measures
- Stress reduction: Chronic stress elevates inflammatory cytokines
- Adequate sleep: Sleep deprivation increases TNF-alpha
- Regular exercise: Anti-inflammatory effects of moderate activity
- Weight management: Obesity increases systemic inflammation
For Psoriasis Prevention/Management
- Identify and avoid personal triggers
- Moisturize regularly to support skin barrier
- Manage stress (major trigger for flares)
- Consider vitamin D optimization (helps many with psoriasis)
- Limit alcohol (associated with worse psoriasis)
Supplements to Consider
- Fish oil: 2-4g EPA+DHA daily
- Vitamin D: Immune modulation, skin benefits
- Curcumin: Bioavailability-enhanced formulations
- Probiotics: Gut-skin axis modulation
Prevalence
- A allele frequency: Approximately 5-10% in most populations
- A/A genotype: Rare (less than 1%)
- Population variation: Some differences across ancestries
Testing Considerations
When to Consider Testing
- Family history of psoriasis
- Personal history of inflammatory skin conditions
- Unexplained chronic inflammation
- Considering anti-TNF therapy
Interpreting Results
- Should be interpreted with G-308A results
- Environmental factors still major determinants
- Genetic risk doesn't equal destiny
- Actionable for prevention strategies
Testing with NutraHacker
NutraHacker's Skincare Panel analyzes both TNF promoter variants along with other inflammation and skin health genes, providing a comprehensive view of your inflammatory genetics.
Frequently Asked Questions
If I have the A allele, will I definitely get psoriasis?
No. While the A allele increases psoriasis risk, many carriers never develop the condition. Psoriasis requires both genetic susceptibility and environmental triggers. Factors like stress, infections, medications, and lifestyle all influence whether someone with genetic risk actually develops psoriasis. Knowing your risk can motivate preventive measures.
How is this different from the G-308A variant?
Both are in the TNF promoter but at different positions with different functional effects. G-308A (rs1800629) clearly increases TNF production and is associated broadly with autoimmune diseases. G-238A (rs361525) has more complex effects and particularly strong psoriasis associations. Analyzing both gives a more complete picture of TNF-related inflammation genetics.
Can I do anything to reduce my psoriasis risk if I carry this variant?
Yes. Maintain healthy weight, manage stress effectively, don't smoke, limit alcohol, support your skin barrier with moisturizers, ensure adequate vitamin D, eat an anti-inflammatory diet rich in omega-3s, and address any infections promptly. These measures can reduce the likelihood of triggering psoriasis even with genetic susceptibility.
References
- Reich K, et al. Tumor necrosis factor polymorphisms in psoriasis. J Invest Dermatol. 2002;119(2):326-336.
- Höhler T, et al. A TNF-alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis. J Invest Dermatol. 1997;109(4):562-565.
- Nedoszytko B, et al. The role of tumor necrosis factor-alpha promoter polymorphisms in psoriasis. Arch Immunol Ther Exp. 2007;55(6):399-403.