This Gene May Contribute to 3 Inflammatory Gut Conditions (NOTCH4)

NOTCH4 (neurogenic locus notch homolog 4) is the gene coding for a protein of the same name, notch4. Notch4 is one of the four notch proteins in mammals, which are deeply involved in cell growth and development from embryo to adult [R, R].

Notch4, unlike the other notch proteins, is mainly expressed in the circulatory system. It is essential for angiogenesis: the process of growing and developing new blood vessels. Poorly regulated angiogenesis is implicated in a huge variety of disorders and diseases, including cancer, psoriasis, arthritis, and even blindness [R].

Gut disorders like IBS, IBD, and celiac disease are often marked by irregular patterns of angiogenesis. In celiac disease, a person’s immune system may produce antibodies that bind to TG2, a protein that (like notch4) is required for the production of new blood vessels. Some researchers believe that these autoantibodies activate TG2 and cause dysregulated or inhibited angiogenesis [R, R, R, R, R, R].

By contrast, chronic gut inflammation in general is characterized by excessive angiogenesis; inflammatory processes require an abundance of tiny blood vessels transporting inflammatory cytokines and white blood cells into the area [R].

Notch4 is also not expressed in the actual intestinal lining, but it is abundant in the blood vessels that feed and transport nutrients away from the intestines. One gene expression study found that in cases of acute celiac disease, NOTCH4 was lower than normal in the lining of the small intestine; other studies note that notch4 promotes NF-kB inflammatory signalling, suggesting that higher notch4 activity would be expected in inflammatory gut diseases [R, R, R].

Surprisingly, there is very little research on a potential direct connection between notch4, angiogenesis, and IBD. Rather, much of the research on notch4 focuses on how it may increase inflammation in other diseases. There is quite a bit of variation in the effect of notch4 in different tissues, but for the most part, it appears to stimulate inflammatory cascades [R, R, R].

While the mechanisms for the link have been somewhat elusive, NOTCH4 variants have been associated with celiac disease and both major forms of IBD.

Notch4 regulates angiogenesis, the growth and development of new blood vessels. Inflammatory gut diseases may be characterized by too much or too little angiogenesis, which may be linked to high or low notch4.

What is IBD?

IBD is a group of autoimmune diseases characterized by inflammation and sores in the gut lining, which can result in diarrhea, abdominal pain, fatigue, fever, rectal bleeding, nutritional deficiencies, and weight loss. The definition of IBD includes both ulcerative colitis and Crohn’s disease [R].

Crohn’s disease differs from ulcerative colitis in that it is centered higher in the digestive tract (typically in the small intestine, though it can occur anywhere between the mouth and anus) and may damage broader swaths of tissue [R, R].

By contrast, ulcerative colitis (UC) produces chronic inflammation and ulceration of the large intestine (the colon) and is also focused on the innermost lining of the colon wall, where Crohn’s can damage much broader swaths of tissue [R, R, R].

What is Celiac Disease?

Celiac disease is an autoimmune disorder wherein the body produces a diseased inflammatory response in response to gluten. It can have symptoms very similar to IBS or IBD (bloating, diarrhea, constipation, nausea, pain, weight loss, etc.), but it can often be identified by testing for anti-gluten antibodies [R].

People who are diagnosed with celiac disease must observe a gluten-free diet and avoid all products containing gluten to prevent inflammatory reactions and flare-ups [R].

NOTCH4 & Celiac Disease

One NOTCH4 variant has been associated with celiac disease so far. At rs424232, the common ‘C’ allele is more common in celiac disease patients than in the general population. The uncommon ‘T’ allele, on the other hand, may be somewhat protective against celiac disease [R].

We should note that this SNP is generally linked to NOTCH4, but it is also nearby to and often inherited with HLA-DRB1, an important immune system gene. It is therefore possible that HLA-DRB1 is the cause of rs424323’s association with celiac disease. Regardless, this SNP is a useful tag for identifying a potential predisposition to celiac disease [R].

NOTCH4 & IBD

Two NOTCH4 variants have been associated with inflammatory bowel disease. At rs549182, the rare ‘A’ allele has been associated with ulcerative colitis; at rs9267911, the common ‘T’ allele has been associated with Crohn’s disease [R, R].

Variants of NOTCH4 have been associated with ulcerative colitis, Crohn’s disease, and celiac disease.

SNP Summary and Table

NOTCH4 rs424232

• ‘C’ = Potentially decreased small blood vessel growth, associated with Celiac disease in a Swedish & Norwegian study
• ‘T’ = Not associated with Celiac disease
• About 47% of all people worldwide have the ‘CC’ genotype.
• The ‘CC’ genotype is similarly distributed all around the world, with the lowest frequency in South Asian populations (41%) and the highest in American populations (55%).

NOTCH4 rs549182

• ‘G’ = Not associated with ulcerative colitis
• ‘A’ = Associated with ulcerative colitis in an Indian study
• Only about 15% of all people worldwide have at least one copy of the ‘A’ allele.
• The ‘A’ allele is significantly more common in people of South Asian descent (25%) and significantly less common in people of European descent (5%).

NOTCH4 rs9267911

• ‘T’ = Associated with Crohn’s disease in a Japanese study
• ‘C’ = Not associated with Crohn’s disease
• About 21% of people worldwide have the possibly protective ‘CC’ genotype.
• The ‘CC’ genotype is similarly distributed around the world, with the lowest frequency in African populations (16%) and the highest in South Asian populations (28%).