TNF-alpha: Inflammation and Your Genes

Do you feel like you are always dealing with inflammation? Joint pain, food sensitivity, skin issues, gum disease, etc… It could be that your body genetically gears towards a higher inflammatory response due to high TNF-alpha levels.

Tumor necrosis factor (TNF) is an inflammatory cytokine that acts as a signaling molecule in our immune system. In an acute inflammatory situation, TNF-alpha plays an essential role in protecting us, but genetically higher TNF-alpha levels are also linked to chronic inflammatory diseases.

What is Tumor Necrosis Factor- Alpha?

TNF-alpha is an inflammatory cytokine produced by the immune system cells (macrophages) during acute inflammation. The main role of this cytokine involves signaling for ‘apoptosis’ meaning the cell needs to be destroyed.[ref]

Inflammatory signaling molecule: Calling in the troops

We think of redness, swelling, heat, and pain with inflammation such as after getting a cut or wound. The inflammatory response is also important for fighting off bad bacteria, viruses, or fungus.  When the body needs an inflammatory response to fight off an invader, it releases cytokines, such as TNF-alpha (and others).

When TNF-alpha binds to its receptor on the surface of a cell, one option is that kills the cell. Kind of 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.

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

TNF-alpha is an essential part of the body’s initial defense against pathogens such as tuberculosis, histoplasmosis, malaria, and leprosy.[ref][ref][ref][ref]

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. Two main receptors are TNFR1 and TNFR2. Most cells in the body have the TNFR1 receptor, but the TNFR2 receptor is found mainly in immune system cells.[ref]

TNF binding to the receptor can cause several different actions to occur, depending on the cell type and receptor type:

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

Higher levels of TNF-alpha and chronic inflammation:

In fact, some of the 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.

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 TB (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
  • psoriasis
  • IBD (ulcerative colitis, Crohn’s disease)
  • skin infections
  • gum disease
  • asthma
  • diabetic ulcers
  • heart disease
  • septic shock
  • depression
  • COPD
  • neurodegenerative diseases

 

Studies relate TNF-alpha to a number of chronic inflammatory conditions:

Depression, inflammation, and TNF-alpha:

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]

Researchers think that inflammation, specifically the 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]

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 turn to genetics. Studies show variants that increase TNF are causally linked to an increased risk of heart disease.[ref]

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 life. 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]

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 decreases the receptor needed for the absorption of vitamin C (SLC23A1).[ref]
  • Short-chain fatty acids, such as butyrate, are important in 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 the microglia and astrocytes, further perpetuating the creation of TNF-alpha and other inflammatory cytokines.[ref][ref]

Fatty liver disease:

Non-alcoholic fatty liver disease 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]


TNF Gene Variants: SNPs linked to inflammation

Member’s Visual Overview:

A quick overview of the TNF-related genes (details below).
Members: Log in to see your data below Not a member? Join now.

Gene RS ID Risk Allele YOU Notes about the Risk Allele:
TNF rs1800629 A Higher TNF-alpha.
TNF rs361525 A Higher TNF-alpha.
TNF rs1799964 C Higher TNF-alpha.  I
TNF rs1799724 T Somewhat higher
TNF rs1800610 A Lower TNF-alpha
TNFRSF1A rs1800693 C Increased inflammation risk
TNFRSF1A rs767455 C Increased inflammation risk
TNFRSF1B rs1061622 G Increased inflammation risk

 

TNF gene 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 (23andMe 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], stroke[ref], gum disease[ref], heart disease[ref]; nasal polyps[refLower risk of:  Malaria (half the risk)[ref], osteoporosis[ref],  stroke[ref]
  • A/G: somewhat higher TNF-alpha levels – see  above
  • G/G: typical, better response to high protein/low carb diet

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 (23andMe 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; AncestryDNA):

  • 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 for reducing chronically high 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 as a way to reduce chronic inflammation. If you are at a higher risk of infections, talk to your doctor.

Natural TNF-alpha inhibitors:

Always check with your doctor or pharmacist if you are on medications before beginning a new supplement. Several of these TNF-alpha inhibitors can lower blood pressure and may interact with medications.

Rosmarinic acid (found in rosemary, basil, holy basil, lemon balm, and perilla oil) is a natural TNF-alpha inhibitor.[ref] In addition to adding herbs to your food, holy basil can be found in a tea (called Tulsi tea) or as a supplement. Examine.com has good information on rosmarinic acid.

Curcumin, found in turmeric, is a natural TNF-alpha inhibitor.[ref]

Resveratrol is another natural flavonoid that has shown in studies to decrease TNF. It is thought to work via increasing SIRT1.[ref][ref]

Probiotics containing Bifidobacteria or Lactobacillus may decrease TNF-alpha levels.[ref] One study showed that B. adolescentis decreased TNF-alpha levels and had an antidepressant effect.[ref] In kids with celiac disease, Bifidobacterium breve BR03 decreased TNF-alpha levels.[ref] Lactobacillus Plantarum restores tight junctions (decrease leaky gut) in the intestines. It is also decreased TNF-alpha.[ref][ref]

Glycine has shown to reduce TNF-alpha and inflammation.[ref] Glycine is an amino acid that is abundant in bone broth, collagen, and gelatin. My favorite way to increase my intake of gelatin is to dissolve it in my coffee each morning.

Magnesium: Low magnesium levels may play a role in higher TNF-alpha levels. Magnesium sulfate, in conjunction with thyroid medication, in hypothyroid rats, decreased TNF-alpha levels.[ref][ref]

Luteolin: In a study of children with autism spectrum disorder, luteolin supplementation has shown to decrease the elevated TNF levels significantly. The supplement used in the study was NeuroProtek.[ref]

Hesperidin, a natural flavonoid from citrus fruits, inhibits the release of TNF-alpha.[ref]

Aged garlic extract has shown in a study to decrease TNF-alpha levels by 35%.[ref][ref] You can find aged black garlic at grocery stores, and it is available as a supplement online if you don’t like the taste of aged garlic.

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]

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]


Related Articles and Topics:

CTLA-4: Autoimmune Genetic Risk
The CTLA4 gene codes for a protein that is important in the immune system. It acts as a checkpoint that can downregulate your immune system response. Genetic variants in the CTLA4 gene can increase your risk for several different autoimmune diseases.

Psoriasis Genes
Psoriasis is an autoimmune condition that causes dry, sometimes itchy patches of skin. It is caused by the immune system attacking your skin cells, speeding up the turnover of the cells. Genetics plays a role in your susceptibility



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.