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 is genetically geared 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 (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.[ref]

Inflammatory signaling molecule: Calling in the troops

We think of redness, swelling, heat, and pain as 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 it kills the cell. 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:[ref][ref][ref][ref]

  • tuberculosis
  • histoplasmosis
  • malaria
  • leprosy

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 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:

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 chronic inflammatory conditions

Chronic inflammation can be a driving factor in many diseases, such as:

  • depression
  • heart disease
  • fibroid
  • neurodegenerative diseases
  • fatty liver disease (NAFLD)

Let’s dive into the research here:

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 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]

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 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 Gene Variants: SNPs linked to inflammation

Members: Log in to see your data below
Not a member? Join now to see your data and member’s only sections.

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], tuberculosis[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 to reduce chronic inflammation. If you are at a higher risk for 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. has good information on rosmarinic acid.

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

Resveratrol is another natural flavonoid that has been 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 also decreased TNF-alpha.[ref][ref]

Glycine has been shown to reduce TNF-alpha and inflammation.[ref] Glycine is an amino acid that is abundant in bone broth, collagen, and gelatin.

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 been shown to decrease 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][ref] (Read more about hesperidin.)

Aged garlic extract has been 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]

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]

Member’s Blueprint: Next Steps and Experiments

Member Content:

An active subscription is required to access this content.

Join Here for full access to this article and more!

Member Benefits:

Read this Member's Only section.

See your genotype in each article.

Print out topic summary reports.

Already a member? Please log in below.

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

Longevity Lifehacks: TNF-alpha and Inflammaging
Learn more about how chronically elevated TNF-alpha is a cause of chronic disease in aging.

Always tired? Genetic reasons for fatigue
Are you always tired even when you know you slept well? Discover more about the newest research on fatigue and how genetic susceptibility plays a part for some people.


Allendoerfer, Ruth, and George S. Deepe. “Blockade of Endogenous TNF-α Exacerbates Primary and Secondary Pulmonary Histoplasmosis by Differential Mechanisms.” The Journal of Immunology, vol. 160, no. 12, June 1998, pp. 6072–82.,

Borthakur, Alip, et al. “The Probiotic Lactobacillus Plantarum Counteracts TNF-{alpha}-Induced Downregulation of SMCT1 Expression and Function.” American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 299, no. 4, Oct. 2010, pp. G928-934. PubMed,

Chen, Huacong, et al. “Tumor Necrosis Factor-Alpha Impairs Intestinal Phosphate Absorption in Colitis.” American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 296, no. 4, Apr. 2009, pp. G775-781. PubMed,

Chen, Yihe, and Kuifen Ma. “NLRC4 Inflammasome Activation Regulated by TNF-α Promotes Inflammatory Responses in Nonalcoholic Fatty Liver Disease.” Biochemical and Biophysical Research Communications, vol. 511, no. 3, Apr. 2019, pp. 524–30. PubMed,

Ciebiera, Michał, et al. “The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms.” International Journal of Molecular Sciences, vol. 19, no. 12, Dec. 2018, p. 3869. PubMed Central,

—. “The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms.” International Journal of Molecular Sciences, vol. 19, no. 12, Dec. 2018, p. 3869. PubMed Central,

Culjak, Marija, et al. “The Association between TNF-Alpha, IL-1 Alpha and IL-10 with Alzheimer’s Disease.” Current Alzheimer Research, vol. 17, no. 11, 2020, pp. 972–84. PubMed,

Dhamodharan, Umapathy, et al. “Genetic Association of IL-6, TNF-α and SDF-1 Polymorphisms with Serum Cytokine Levels in Diabetic Foot Ulcer.” Gene, vol. 565, no. 1, July 2015, pp. 62–67. PubMed,

Ding, Cheng, et al. “TNF-α Gene Promoter Polymorphisms Contribute to Periodontitis Susceptibility: Evidence from 46 Studies.” Journal of Clinical Periodontology, vol. 41, no. 8, Aug. 2014, pp. 748–59. PubMed,

Durães, Cecília, et al. “Polymorphisms in the TNFA and IL6 Genes Represent Risk Factors for Autoimmune Thyroid Disease.” PloS One, vol. 9, no. 8, 2014, p. e105492. PubMed,

—. “Polymorphisms in the TNFA and IL6 Genes Represent Risk Factors for Autoimmune Thyroid Disease.” PloS One, vol. 9, no. 8, 2014, p. e105492. PubMed,

Feng, Bo, et al. “Association of Tumor Necrosis Factor α -308G/A and Interleukin-6 -174G/C Gene Polymorphism with Pneumonia-Induced Sepsis.” Journal of Critical Care, vol. 30, no. 5, Oct. 2015, pp. 920–23. PubMed,

Frankola, Kathryn A., et al. “Targeting TNF-Alpha to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases.” CNS & Neurological Disorders Drug Targets, vol. 10, no. 3, May 2011, pp. 391–403. PubMed Central,

Gichohi-Wainaina, Wanjiku N., et al. “Tumour Necrosis Factor Allele Variants and Their Association with the Occurrence and Severity of Malaria in African Children: A Longitudinal Study.” Malaria Journal, vol. 14, June 2015, p. 249. PubMed,

Idriss, H. T., and J. H. Naismith. “TNF Alpha and the TNF Receptor Superfamily: Structure-Function Relationship(s).” Microscopy Research and Technique, vol. 50, no. 3, Aug. 2000, pp. 184–95. PubMed,<184::AID-JEMT2>3.0.CO;2-H.

Kakino, Satomi, et al. “Pivotal Role of TNF-α in the Development and Progression of Nonalcoholic Fatty Liver Disease in a Murine Model.” Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme, vol. 50, no. 1, Jan. 2018, pp. 80–87. PubMed,

Khan, Saif, et al. “TNF-α -308 G > A (Rs1800629) Polymorphism Is Associated with Celiac Disease: A Meta-Analysis of 11 Case-Control Studies.” Scientific Reports, vol. 6, Sept. 2016, p. 32677. PubMed,

Locksley, Richard M., et al. “The TNF and TNF Receptor Superfamilies: Integrating Mammalian Biology.” Cell, vol. 104, no. 4, Feb. 2001, pp. 487–501.,

Ma, Ke, et al. “Pathogenetic and Therapeutic Applications of Tumor Necrosis Factor-α (TNF-α) in Major Depressive Disorder: A Systematic Review.” International Journal of Molecular Sciences, vol. 17, no. 5, May 2016, p. 733. PubMed Central,

MacIntyre, Elaina A., et al. “GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study.” Environmental Health Perspectives, vol. 122, no. 4, Apr. 2014, pp. 418–24. PubMed,

Majumder, Poulami, et al. “Association of Tumor Necrosis Factor-α (TNF-α) Gene Promoter Polymorphisms with Aggressive and Chronic Periodontitis in the Eastern Indian Population.” Bioscience Reports, vol. 38, no. 4, Aug. 2018, p. BSR20171212. PubMed,

Olszewski, Maciej B., et al. “TNF Trafficking to Human Mast Cell Granules: Mature Chain-Dependent Endocytosis.” Journal of Immunology (Baltimore, Md.: 1950), vol. 178, no. 9, May 2007, pp. 5701–09. PubMed,

“Pathophysiology of Autoimmune Diseases and Inflammation.” AJMC, Accessed 10 Dec. 2021.

Randall, Louise M., and Christian R. Engwerda. “TNF Family Members and Malaria: Old Observations, New Insights and Future Directions.” Experimental Parasitology, vol. 126, no. 3, Nov. 2010, pp. 326–31. ScienceDirect,

—. “TNF Family Members and Malaria: Old Observations, New Insights and Future Directions.” Experimental Parasitology, vol. 126, no. 3, Nov. 2010, pp. 326–31. ScienceDirect,

Reséndiz-Hernández, Juan Manuel, et al. “Identification of Genetic Variants in the TNF Promoter Associated with COPD Secondary to Tobacco Smoking and Its Severity.” International Journal of Chronic Obstructive Pulmonary Disease, vol. 10, 2015, pp. 1241–51. PubMed,

Stappers, M. H. T., et al. “Polymorphisms in Cytokine Genes IL6, TNF, IL10, IL17A and IFNG Influence Susceptibility to Complicated Skin and Skin Structure Infections.” European Journal of Clinical Microbiology & Infectious Diseases: Official Publication of the European Society of Clinical Microbiology, vol. 33, no. 12, Dec. 2014, pp. 2267–74. PubMed,

Subramanian, Veedamali S., et al. “Tumor Necrosis Factor Alpha Reduces Intestinal Vitamin C Uptake: A Role for NF-ΚB-Mediated Signaling.” American Journal of Physiology – Gastrointestinal and Liver Physiology, vol. 315, no. 2, Aug. 2018, pp. G241–48. PubMed Central,

Tavares, M., et al. “Tumour Necrosis Factor-Alpha (-308G/A) Promoter Polymorphism Is Associated with Ulcerative Colitis in Brazilian Patients.” International Journal of Immunogenetics, vol. 43, no. 6, Dec. 2016, pp. 376–82. PubMed,

Ueda, Mayu, et al. “A Short-Term Treatment with Tumor Necrosis Factor-Alpha Enhances Stem Cell Phenotype of Human Dental Pulp Cells.” Stem Cell Research & Therapy, vol. 5, no. 1, Feb. 2014, p. 31. PubMed Central,

Wu, Jun-Cang, et al. “Gene Polymorphisms and Circulating Levels of the TNF-Alpha Are Associated with Ischemic Stroke: A Meta-Analysis Based on 19,873 Individuals.” International Immunopharmacology, vol. 75, Oct. 2019, p. 105827. PubMed,

Yucesoy, Berran, et al. “Genetic Variants in TNFα, TGFB1, PTGS1 and PTGS2 Genes Are Associated with Diisocyanate-Induced Asthma.” Journal of Immunotoxicology, vol. 13, no. 1, 2016, pp. 119–26. PubMed,

Zhang, Guimin, et al. “The Role of TNF Alpha Polymorphism and Expression in Susceptibility to Nasal Polyposis.” Immunological Investigations, vol. 47, no. 4, May 2018, pp. 360–71. Taylor and Francis+NEJM,

Zhang, Peng, et al. “Tumor Necrosis Factor-Alpha Gene Polymorphisms and Susceptibility to Ischemic Heart Disease.” Medicine, vol. 96, no. 14, Apr. 2017, p. e6569. PubMed Central,

—. “Tumor Necrosis Factor-Alpha Gene Polymorphisms and Susceptibility to Ischemic Heart Disease.” Medicine, vol. 96, no. 14, Apr. 2017, p. e6569. PubMed Central,

About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.