Could This Inflammation Gene Affect Thyroid Health? (TNF)

The TNF gene is responsible for coding a protein called tumor necrosis factor alpha (also referred to as TNF-alpha or cachexin) [R].

The TNF-alpha protein is a cytokine, a type of protein involved in cell signaling. It plays a major role in the body’s immune and inflammatory response [R].

TNF-alpha is produced by many components of the immune system, including [R]:

• Macrophages
• Natural killer (NK) cells
• Neutrophils
• Mast cells

Variants in the TNF gene can lead to improper levels of TNF-alpha in the body. These genetic variations have been associated with several health conditions, such as thyroid disorder, autoimmune diseases, and cancer [R, R, R].

The TNF gene helps create TNF-alpha, which plays a role in regulating cells in the immune system. It has several functions throughout the body, many of which are in combination with IL-1 and IL-6 (other types of cytokines) [R].

Some of the effects of TNF-alpha include [R]:

• Inducing inflammation and fever
• Suppressing appetite
• Stimulating phagocytosis, the process which eliminates harmful substances like bacteria from the body

TNF-alpha works by binding to specific receptors that activate various cell signaling pathways, such as the MAPK pathway [R].

According to research, the TNF gene may play an important role in thyroid health. 

Studies show that certain genetic variants of TNF may be associated with thyroid disorders, such as Graves’ disease and Hashimoto’s disease [R].

In the following sections, we’ll detail how variants in TNF are connected to these thyroid conditions and why this association may exist.

Graves’ Disease

Graves’ disease is an autoimmune disorder that affects the thyroid gland. It leads to the overproduction of thyroid hormones, otherwise known as hyperthyroidism [R].

Several different genetic variations of TNF have been associated with Graves’ disease. We’ll go over each of these variants and who they affect in the sections below.

TNF -308 (rs1800629)

Certain genotypes in rs1800629 (also known as TNF -308) may be linked to higher rates of Graves’ disease, according to research.

For example, one systematic review of 10 studies looked at the TNF gene of over 6,000 people. Researchers found that the ‘AA’ genotype in rs1800629 may be associated with Graves’ disease in European populations. However, an association was not found in Asians [R].

Likewise, a study of over 1,200 subjects also revealed a link between Graves’ disease and the ‘AA’ genotype in rs1800629, this time in a Portuguese population [R].

The same association may be present in Tunisian groups, according to a study of 305 people [R].

TNF -1031 (rs1799964)

Research suggests that rs1799964 (commonly referred to as TNF -1031) may also be connected to thyroid health.

A study of 75 patients with Graves’ disease and 70 healthy controls (all from a Japanese population) found that the ‘C’ allele was significantly more common in those with thyroid disorder [R].

Similar results have been found in other research, including a meta-analysis of 10 case-control studies that found the same association between rs1799964 and Grave’s disease in a Chinese population [R].

TNF -863 (rs1800630)

According to a meta-analysis of 10 studies with over 2,200 Graves’ disease patients and 2,600 healthy controls, the ‘A’ allele of rs1800630 is more commonly found in Chinese and Thai people with thyroid disorder [R].

TNF -238 (rs361525)

The ‘A’ allele in rs361525 (also known as TNF -238) was associated with a higher risk of Graves’ disease in Taiwanese patients, based on one study of 326 subjects [R].

Another study of over 1,700 Caucasians from the U.K. found the same link between Graves’ disease and the ‘A’ allele [R].

However, there are other studies that have not found a significant link between this variant and Graves’ disease in Asian and European populations [R].

To further complicate things, one study found that the ‘G’ allele was actually more prevalent in Chinese patients with Graves’ disease [R].

Hashimoto’s Disease

Similar to Graves’ disease, Hashimoto’s disease is an autoimmune disorder that affects the thyroid [R]. 

However, in the case of Hashimoto’s disease, the immune system mistakenly damages the thyroid gland, leading to reduced release of thyroid hormones, also called hypothyroidism [R].

There are several TNF variants that may be associated with an increased risk of Hashimoto’s disease, which we’ll describe below.

TNF -308 (rs1800629) 

A study of over 1,100 Portuguese patients suggests that the ‘A’ allele in rs1800629 is associated with Hashimoto’s disease [R].

TNF -1031 (rs1799964)

A smaller study of 77 Japanese subjects with Hashimoto’s disease found that the ‘C’ allele in rs1799964 is more common in people with this thyroid disorder [R].

However, researchers also discovered that the ‘C’ allele is not associated with the severity of Hashimoto’s disease [R].

How Do TNF Variants Affect The Thyroid?

Research shows that certain variants of the TNF gene, such as rs1800629, can lead to increased production of TNF-alpha in the body [R].

This rise in TNF-levels may alter how the immune system works, which potentially increases the risk for thyroid-related autoimmune disorders, such as Graves’ and Hashimoto’s disease [R].

In fact, the different variants of TNF that have been listed may also be associated with many other health conditions, such as:

• Asthma and COPD [R, R]
• Heart disease [R]
• Rheumatoid arthritis [R, R]
• Systemic lupus erythematosus (SLE) [R]
• Cancer [R, R]

You can see your genotypes for TNF in the table below. However, keep in mind that these associations are based on studies from certain ethnic populations — so you should interpret your results with caution if you are not descended from one of these specific groups!

Primary SNPs:

TNF rs1800629

• ‘G’ = Not associated with thyroid disorders
• ‘A’ = Associated with Graves’ and Hashimoto’s disease
• This association has only been found in certain European, Portuguese, and Tunisian populations
• This association was not found in Asian populations
• About 17% of people have at least one ‘A’ allele

TNF rs1799964

• ‘T’ = Not associated with thyroid disorders 
• ‘C’ = Associated with Graves’ and Hashimoto’s disease
• This association has only been found in certain Japanese and Chinese populations
• About 39% of people have at least one ‘C’ allele

TNF rs1800630

• ‘C’ = Not associated with thyroid disorders 
• ‘A’ = Associated with Graves’ disease
• This association has only been found in certain Chinese and Thai populations
• About 28% of people have at least one ‘A’ allele

TNF rs361525

• ‘G’ = Not associated with thyroid disorders 
• ‘A’ = Associated with Graves’ disease
• This association has only been found in certain Taiwanese and Caucasian populations
• About 12% of people have at least one ‘A’ allele