How Much Does This Gene Influence Your Detox System? (NFE2L2)

The NFE2L2 gene is responsible for encoding a protein called NRF2, which plays a major role in your body’s detoxification process. More specifically, NRF2 is responsible for activating many of your other genes that produce detox proteins [R].

Certain genetic variations of NFE2L2 can reduce the expression and activity of NRF2; in turn, lower NRF2 expression may prevent the body from detoxing compounds that cause oxidative stress. According to some researchers, impaired NRF2 could potentially lead to several conditions, such as liver disease, Parkinson’s, and cancer [R].

The NFE2L2 gene encodes NRF2, a protein that controls the expression of many other antioxidant and detox genes.

How Does NRF2 Regulate Detox?

NRF2 is central to the body’s defense against oxidative stress, but it does not have antioxidant activity itself. Instead, NRF2 activates other genes that code for antioxidant proteins. It does this by binding to an area of other genes called the “antioxidant response element” (ARE), which increases expression of that gene [R, R].

Some important antioxidant genes that are activated by NRF2 include [R, R]:

• NQO1: detoxes quinones, which can cause oxidative stress
• UGT: detoxes plastics, drugs, and many of the body’s waste products
• GST: supports glutathione, an important antioxidant
• GCLC and GCLM: help in the production of glutathione
• HO-1: helps in the breakdown of red blood cell components

NRF2 regulates the production of antioxidant proteins that clear out toxins from the body.

Hijacked by Cancer

Generally, increasing NRF2 is thought of as beneficial because of its detox function. However, some studies have also found that cancer cells take advantage of increased NRF2 activation to make themselves more resistant to treatment [R, R].

Cancer cells may be able to use the NRF2 in the body to detox themselves from anticancer medications, leading to drug resistance. Thus, NRF2 may help prevent cancer in healthy people, but existing cancer cells can hijack it to protect themselves. This is not to say that NRF2 is detrimental to people with cancer, however: cancer cells simply take advantage of beneficial mechanisms and natural defenses to make themselves more potent [R, R].

NRF2 activation reduces the risk of cancer development, but it may also protect cancer cells from drug treatment.

Research has identified several variations in the NFE2L2 gene that can reduce the expression and activity of NRF2. Some researchers have claimed that reduced NRF2 impairs the body’s ability to detox and defend itself from oxidative stress, which can ultimately lead to various health problems. In the following sections, we’ll list out some of these important health outcomes and what genetic variations may influence them [R].

Alcohol Toxicity

Alcohol consumption produces reactive oxygen species that cause oxidative stress and inflammation, especially in the liver. In a healthy person, NRF2 protects the liver from oxidative injury, but certain variations in NFE2L2 can disrupt this detox process. In some studies, disrupted detox has been linked to liver disease, hepatitis, and cirrhosis [R].

One study found that the SNP rs35652124 is associated with oxidative damage to the liver. Alcoholic liver disease is more common among people with the ‘T’ allele than those with the ‘C’ allele. Additional research will be required to determine the exact role of this variant in the development of this disease [R].

Certain genetic variations in NFE2L2 have been associated with alcohol toxicity and liver disease.

Drug and Environmental Toxicity

NRF2 regulates the expression of many proteins that are responsible for clearing out toxins that come from medications and the environment. One study found that those with a ‘TT’ genotype in rs35652124 are 52% more likely to experience drug toxicity compared to other genotypes [R].

Exposure to environmental toxins, such as certain metals, can cause several illnesses if not treated properly. According to one study, the ‘T’ allele in both rs35652124 and rs6721961 is associated with worse health outcomes from arsenic exposure [R].

Certain sources of drinking water may be contaminated with arsenic, which may in turn increase the risk of cancer and other diseases [R].

Variants in NFE2L2 may impair the body’s ability to remove toxins that come from drugs and the environment. Some researchers conclude that these variants may lead to toxicity symptoms.

Parkinson’s Disease

The cause of Parkinson’s disease isn’t fully understood, but many researchers believe that oxidative stress is a significant factor. For this reason, much effort has been made to identify the connection between NRF2 and this disorder [R].

The results of genetic studies have been mixed: some research implies that there is evidence of variants in NFE2L2 increasing the risk of Parkinson’s, while other studies found no association. One analysis of six studies found that variations at rs6721961 and rs2886161 are more common in people who develop Parkinson’s disease. This analysis also found a lower age of disease onset in people with these variants [R, R, R].

Gene variants of NFE2L2 are more common in people who develop Parkinson’s disease. They are also associated with lower age of when the disease appears.

Cancer

Prolonged oxidative stress can cause DNA damage, which increases the risk of cancer. Several variants of NFE2L2 have been implicated in multiple types of cancer. For example, one study found that people with the ‘TT’ genotype in rs6721961 had breast cancer at 4.6 times the rate of other genotypes [R, R].

Besides breast cancer, various studies have found associations between NFE2L2 and other cancers, including:

• Lung cancer [R]
• Bile duct cancer [R]
• Pancreatic cancer [R]

Variants in the NFE2L2 gene are more common in people who develop several types of cancer, including breast, lung, and pancreatic cancers.

Other Conditions

Because NRF2 exerts such a broad influence on the body’s detox systems, some researchers believe that genetic variations in NFE2L2 could have far-reaching health consequences. Some other conditions that have been associated with NFE2L2 variants include [R]:

• Lung disorders, such as asthma and COPD
• Heart disease
• Stomach disorders
• Autoimmune disorders

The exact links between NFE2L2 and these conditions have not been fully explained. Future research will clarify whether someone’s NFE2L2 variants can really predict disease.

Certain variations in NFE2L2 are more common in people suffering from conditions that affect the lungs, heart, stomach, and immune system.