TNF-alpha: Inflammation, Chronic Diseases, and Genetic Susceptibility

Key takeaways:
~ TNF-alpha (tumor necrosis factor alpha) is an inflammatory cytokine produced by the immune system to fight off pathogens and cancer cells.
~ Chronic elevation of TNF-alpha levels is linked to autoimmune diseases, skin infections, gum disease, heart disease, depression, and neurodegenerative diseases.
~ Genetic variants can increase your susceptibility to chronically elevated TNF-alpha.
~ Understanding your genes can help you find targeted, natural solutions for chronic inflammation.

Members will see their genotype report below, plus natural solutions for elevated TNF levels in the Lifehacks section. Consider joining today.

What is TNF Alpha?

TNF-alpha (tumor necrosis factor alpha) is an inflammatory cytokine produced by certain immune system cells during acute inflammation. The main role of this cytokine involves signaling for ‘apoptosis’ meaning the cell needs to be destroyed. This is important both in fighting off a pathogen as well as in killing cancer cells.[ref]

Inflammatory signaling molecule: Calling in the troops

We think of redness, swelling, heat, and pain as inflammation, such as what happens after getting injured. However, the inflammatory response is also vital in fighting off bad bacteria, viruses, or fungi.

When the body needs an inflammatory response to fight off an invader, it releases inflammatory cytokines, such as TNF-alpha (and others).

When TNF-alpha binds to its receptor on the surface of a cell, two actions can occur:

One option is that it kills the cell. It’s like it pulls the pin on a grenade.
Another option is that it can also cause the cell to produce other inflammatory response molecules, but the cell still survives.

While cell death sounds bad, it is completely necessary to fight off certain infections — or if a cell is cancerous. Thus the “tumor” in tumor necrosis factor (TNF).

Wound healing:
Additionally, TNF-alpha is essential for the initial stages of wound healing. Inflammation is a necessary step for healing injured tissue.[ref]

Pathogen defense:
TNF-alpha is an essential part of the body’s initial defense against pathogens such as:[ref][ref][ref][ref]

Tuberculosis
Histoplasmosis
Malaria
Leprosy

Tumor Necrosis Factor α: Signal and Receptor

TNF-alpha is synthesized and released by activated immune cells – macrophages, lymphocytes, mast cells, and neutrophils. It is also produced as a transmembrane protein, as well as by smooth muscle cells in response to injury.[ref][ref]

After being released by a cell (e.g. mast cell or macrophage), TNF alpha can bind to several different receptors on the surfaces of cells.

The two main TNF-alpha receptors are TNFR1 and TNFR2. Most cells in the body have the TNFR1 receptor, but the TNFR2 receptor is more specific to immune system cells.[ref]

When TNF binds to a receptor, several different actions can occur, depending on the cell type and receptor type:

activates NF-κB, which is a transcription factor that controls cell survival and inflammatory response
activates the MAPK pathways, which are important in the cell cycle and preventing cancer
signals for cell death

How does TNF alpha cause inflammation?

The immune response is all about balance. You want to fight off pathogens with a strong response, but you don’t want a constant inflammatory response continuing when it isn’t needed.

Super fighter:
Genetic variants that increase TNF-alpha levels are linked to being better able to fight off pathogens, such as malaria or hepatitis B.[ref]

But.. That superpower of fighting pathogens and killing cancer cells comes with a price. For example, chronically elevated levels of TNF-alpha are linked with an increased risk of autoimmune diseases, skin infections, and gum disease.

Chronic inflammation in the body:
Several common genetic variants increase TNF-alpha levels and increase the risk of inflammatory conditions. Keep in mind that these same genetic variants that helped your ancestors survive leprosy or tuberculosis (and thus lived to pass on the variant to you), could be at the root of many of the inflammatory conditions that plague us today.[ref]

Higher TNF-alpha is linked to:

Rheumatoid arthritis (RA)
Psoriasis
IBD (ulcerative colitis, Crohn’s disease)
Skin infections
Gum disease
Asthma
Diabetic ulcers
Heart disease
Septic shock
Ankylosing spondylitis
Depression
Arthritis
COPD
Neurodegenerative diseases

Studies relate TNF alpha to chronic diseases:

Chronic inflammation in the body can be a driving factor in many inflammatory-based chronic diseases.

Examples of diseases caused by inflammation include:

Depression and mood disorders
Heart disease
Fibroids
Neurodegenerative diseases
Arthritis
Fatty liver disease (NAFLD)

Let’s dive into the research here:

Inflammation and Depression:

Recent research shows that, for some people, pro-inflammatory cytokines are at the heart of a major depressive disorder. For a subset of patients with depression, TNF alpha is elevated, and blocking TNF-alpha can ameliorate depressive symptoms. A 2008 genome-wide association study found that a TNF genetic variant increases the risk of depression.[ref]

Related article: Depression and Inflammation

Researchers think that inflammation, specifically high TNF alpha levels, impacts the HPA axis and elevates cortisol. HPA axis dysfunction is strongly linked to depression. Additionally, higher TNF-alpha levels can cause increased uptake of serotonin into cells, causing depressive symptoms.[ref]

Related article: HPA axis dysfunction and your genes

Heart disease:

TNF alpha is increased in heart disease, raising the question of whether heart disease causes an increase in TNF-alpha or whether higher TNF-alpha contributes to causing heart disease. To answer this question, researchers turned to genetics. Studies show variants that increase TNF are causally linked to an increased risk of heart disease.[ref]

Related article: Genetics and Coronary Artery Disease

TNF and Uterine fibroids:

Uterine fibroids are benign tumors in the uterus. These are a common occurrence, with estimates ranging from 50-80% of women having fibroids at some point in their lives. The growth of the fibroids is thought to be caused by steroid hormones (estrogen, progesterone), growth factors, cytokines, and chemokines. Research points to TNF-alpha as the most important cytokines involved in fibroid growth.[ref]

Related article: Fibroids genes

Intestinal absorption is altered with high TNF-alpha:

Inflammation and high TNF-alpha levels in the intestines alter the ability to absorb nutrients.

For example:

High TNF-alpha levels decrease the receptor needed for the absorption of vitamin C (SLC23A1).[ref]
Short-chain fatty acids, such as butyrate, are important for colon health. High levels of TNF-alpha decrease the expression of transporters for butyrate (SLC5A8).[ref]
Phosphate absorption is decreased when TNF-alpha is high in the intestines. Low phosphate absorption can cause problems with teeth and bones.[ref]

Neurodegenerative diseases:

Alzheimer’s and Parkinson’s diseases are both linked to higher TNF-alpha production in the brain.

Research shows that microglia and astrocytes release TNF-alpha when activated, and this increases the production of amyloid-beta plaque, which is linked with Alzheimer’s disease. Additionally, amyloid-beta can activate microglia and astrocytes, further perpetuating the creation of TNF-alpha and other inflammatory cytokines.[ref][ref]

Related article: Alzheimer’s APOE genotype

Fatty liver disease:

Non-alcoholic fatty liver disease (NAFLD) is caused by increased fat stored in the liver. This can eventually lead to liver disease. TNF-alpha, as well as a couple of other inflammatory cytokines, are increased in fatty liver disease. Research using animals that were genetically altered to reduce TNF-alpha levels shows that TNF-alpha is a driving factor in fatty liver disease.[ref][ref]

Related article: Fatty liver disease (NAFLD) genes

TNF Genotype Report

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Variants associated with increased TNF-alpha levels:

There are several genetic variants linked to naturally more active TNF-alpha.

Check your genetic data for rs1800629 -308A/G (23 and Me v4, v5; AncestryDNA):

A/A: Higher TNF-alpha levels. Increased risk of: ulcerative colitis[ref] celiac disease[ref] (note – must have HLA type also), septic shock[ref], diabetic foot ulcers[ref], asthma[ref] , Hashimoto’s thyroiditis[ref], skin infections[ref], periodontitis[ref], asthma[ref] in children, COPD[ref], gum disease[ref], heart disease[ref]; nasal polyps[ref] Lower risk of: Malaria (half the risk)[ref], tuberculosis[ref] osteoporosis[ref], stroke[ref]
A/G: somewhat higher TNF-alpha levels – see above
G/G: typical

Members: Your genotype for rs1800629 is —.

Check your genetic data for rs361525 -238A/G (23andMe v4, v5; AncestryDNA):

A/A: higher TNF-alpha levels[ref], increased risk of psoriasis[ref], asthma[ref], COPD[ref], periodontitis[ref] greater severity in cystic fibrosis[ref]
A/G: somewhat higher TNF-alpha levels
G/G: typical

Members: Your genotype for rs361525 is —.

Check your genetic data for rs1799964 -1031T>C (23andMe v4, v5; AncestryDNA):

C/C: (usually) higher TNF-alpha levels[ref][ref], increased risk of IBD[ref], lupus[ref], gum disease[ref]
C/T: somewhat higher TNF-alpha levels
T/T: typical – generally not at higher risk for inflammatory diseases

Members: Your genotype for rs1799964 is —.

Check your genetic data for rs1799724 (23 and Me v4, v5):

T/T: (generally) higher TNF-alpha levels[ref][ref], increased risk of periodontitis[ref] greater severity in cystic fibrosis[ref]
C/T: somewhat higher TNF-alpha levels
C/C: typical – generally not at higher risk for inflammatory diseases

Members: Your genotype for rs1799724 is —.

TNF gene variants associated with decreased TNF-alpha:

Check your genetic data for rs1800610 (AncestryDNA):

G/G: typical
A/G: somewhat lower TNF-alpha; decreased risk of developing sepsis, increased risk hep B, leprosy
A/A: lower TNF-alpha, decreased risk of developing sepsis[ref]; increased risk of hepatitis B infection[ref], increased risk of leprosy[ref]

Members: Your genotype for rs1800610 is —.

TNF-alpha receptor variants:

Genetic variants that increase TNF receptors also impact the risk of inflammatory diseases.

TNFRSF1A gene: codes for a TNF-alpha receptor

Check your genetic data for rs1800693 (23andMe v4, v5; Ancestry.com):

T/T: typical, better response to anti-TNF drugs[ref]
C/T: slightly increased risk of MS
C/C: increase risk of multiple sclerosis[ref][ref] increased NF-kB signaling

Members: Your genotype for rs1800693 is —.

Check your genetic data for rs767455 (23andMe v5; AncestryDNA):

C/C: increased risk of Crohn’s disease[ref]; increased risk of MS[ref]
C/T: increased risk of inflammatory diseases.
T/T: typical

Members: Your genotype for rs767455 is —.

TNFRSF1B gene: codes for a TNF-alpha receptor

Check your genetic data for rs1061622 (23andMe v4, v5; AncestryDNA):

G/G: more severe pulmonary disease in cystic fibrosis[ref]; increased risk of psoriasis, more likely to be a non-responder to anti-TNF therapy[ref][ref]; increased risk of lupus – especially for smokers[ref]
G/T: increased risk of psoriasis, increased risk of lupus
T/T: typical

Members: Your genotype for rs1061622 is —.

Lifehacks: Natural ways to inhibit TNF alpha

If you carry genetic variants related to higher TNF-alpha levels and have a related inflammatory condition, inhibiting TNF-alpha may help to reduce chronic inflammation.[ref]

Keep in mind the tradeoff between TNF-alpha as a response to pathogens and inhibiting TNF-alpha to reduce chronic inflammation. If you are at a higher risk for infections, talk to your doctor.

Lifestyle factors that influence TNF-alpha levels:

Vitamin D may help people with MS and the TNFRSF1A variant. A study found that there was a statistically significant interaction with variant carriers being at high risk for relapse with low vitamin D levels.[ref] Sun exposure on your skin in the middle of the day is needed for vitamin D production. Lacking that, vitamin D supplements are also available.

Exercise exerts part of its anti-inflammatory effects via reducing TNF-alpha.[ref]

High folate vegetable intake decreased TNF-alpha levels in women with the MTHFR C677T TT genotype.[ref]

Cigarette smoking is linked to significantly higher TNF-alpha levels, and this association may be a driving factor in COPD and other chronic inflammatory diseases linked to smoking.[ref][ref]

8 Natural tumor necrosis factor inhibitors:

The rest of this article covers natural TNF inhibitors, next steps to take, and how to prioritize the solutions. It is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.

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