Could This Gene Be Linked To Gut Inflammation? (ATG16L1)

The ATG16L1 gene encodes for a protein with the same name, ATG16L1 (short for autophagy-related protein 16-1). This protein is part of a larger protein complex that carries out autophagy, a process by which the body removes old or damaged cells to make way for new ones. Autophagy is important because it eliminates defective cells, as well as helps recycle old cellular parts to make into new cells [R].

Research has discovered that certain genetic variations in ATG16L1 may lower the activity of the ATG16L1 protein, which could in turn reduce the body’s ability to carry out the process of autophagy. As we will discuss in the next section, this can lead to increased inflammation — especially in the gut. As a result, these variants have been associated with gut disorders such as Crohn’s disease and ulcerative colitis [R].

The ATG16L1 gene codes for a protein that is responsible for clearing out old and damaged cells from the body.

Reduced Elimination of Defective Cells

Genetic variations in ATG16L1 can disrupt autophagy, thereby potentially leading to an increase in the number of improperly-functioning cells throughout the body. When it comes to the gut in particular, this can lead to an elevation in defective Paneth cells, a type of intestinal cell that helps fight harmful bacteria. Without properly-functioning Paneth cells, a build-up of bacteria can occur in the gut, which could in turn contribute to chronic inflammation [R].

Certain variants in ATG16L1 may impair the function of intestinal cells that protect the gut against harmful bacteria. This can lead to elevations in bacteria counts, which in turn can trigger inflammation.

Inflammatory Cytokines

There is evidence that ATG16L1 gene variants can increase the secretion of the pro-inflammatory cytokines IL-1B and IL-18 in human cells. These two cytokines normally play a role in regulating the body’s inflammatory response — but elevations in IL-1B and IL-18 can lead to excessive inflammation [R].

Certain genetic variations in ATG16L1 may increase the secretion of cytokines that promote inflammation.

Protein Interactions

The ATG16L1 protein has an important interaction with NOD2, a protein that helps activate the immune system in response to bacteria. Normally, ATG16L1 helps limit the number of NOD2 proteins in the body to prevent excessive activity. However, research has found that genetic variants in ATG16L1 may impair this ability to keep NOD2 in check, which in turn could lead to elevated inflammation [R, R].

Some variations in the ATG16L1 gene may increase the activity of NOD2, an immune-related protein that also promotes inflammation.

Although it’s not entirely clear which of the above mechanisms are most directly responsible for the inflammation associated with ATG16L1 variants, a number of studies have linked these variants to inflammatory bowel diseases (IBD) — a group of related disorders caused by inflammation in the digestive tract [R, R, R].

The two most common types of IBD are [R]:

• Crohn’s disease: Inflammation of the digestive tract, most commonly affecting the small and large intestines
• Ulcerative colitis: Inflammation and ulcers that primarily affect the colon and rectum

Both of these disorders can involve symptoms such as diarrhea, abdominal pain, rectal bleeding, and weight loss, while also having their own unique symptoms [R].

In the following sections, we’ll talk about the link between ATG16L1 and IBD, as well as other health conditions.

Certain ATG16L1 gene variants have been linked to inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis.

Crohn’s Disease

Research has identified a strong link between ATG16L1 variants and Crohn’s disease. The evidence is strongest for the SNP rs2241880, for which multiple studies have found that the ‘G’ allele is significantly more common in people with Crohn’s disease compared to the ‘A’ allele. However, this association does not appear to be present in Asian populations [R, R, R].

Other SNPs that have also been associated with Crohn’s disease include rs2241879 and rs10210302 [R, R].

Studies show that certain SNPs in ATG16L1, such as rs2241880, may be associated with Crohn’s disease.

Ulcerative Colitis

Studies show that certain variations of ATG16L1 are also associated with ulcerative colitis, although there is less research on this condition compared to Crohn’s disease. Similar to the findings for Crohn’s, it is once again the ‘G’ allele in rs2241880 that appears to be more common in those with ulcerative colitis — although Asian groups once again seem to be unaffected [R, R, R].

There is suggestive evidence that the ‘G’ allele of rs2241880 may also be associated with ulcerative colitis.

Other Health Conditions

There is some preliminary evidence from a number of smaller studies that ATG16L1 gene variants — especially in rs2241880 — may be associated with several other disorders, such as:

• Palmoplantar pustulosis: a chronic skin disorder [R]
• Paget’s disease of bone: a condition that interferes with the bone remodeling process [R]
• Buruli ulcers: a type of chronic ulcer caused by bacterial infections [R]
• Melanoma: a form of skin cancer [R]
• Mouth cancer [R]

It’s important to note that just because certain genotypes are associated with a disease, it doesn’t necessarily mean that everyone with that genotype will actually develop the disease! Many different factors, including other genetic and environmental factors, can influence the risk of inflammatory bowel diseases.

You can see your genetic data for several important ATG16L1 SNPs in the table below:

ATG16L1 rs2241880:

• ‘A’ = Not associated with inflammation
• ‘G’ = Associated with inflammatory conditions
• About 18% of people have the ‘GG’ genotype, which is the genotype that has been most strongly associated with inflammation

ATG16L1 rs10210302:

• ‘C’ = Not associated with inflammation
• ‘T’ = Associated with inflammatory conditions
• About 18% of people have the ‘TT’ genotype, which is the genotype that has been most strongly associated with inflammation

Important note: In Asian populations, none of the variants in ATG16L1 appear to be associated with inflammatory conditions — so take this into consideration when interpreting your results.

Also, these SNPs are often inherited together. For example, if someone has an allele that’s not associated with inflammation (like the ‘A’ allele in rs2241880), they are likely to also carry the non-risk allele in other SNPs (such as ‘G’ in rs2241879 and ‘C’ in rs10210302).