Ulcerative colitis: what gut cell mutations reveal and how genes affect UC medications

Ulcerative colitis (UC) is a chronic inflammatory disease of the large intestine (colon and rectum) that causes diarrhea, bleeding, urgency and abdominal pain, often in flares. Genes, gut bacteria, diet and other environmental factors all play a part. Research into how long-lasting inflammation changes the cells lining the colon is helping explain why UC raises the risk of colorectal cancer. Meanwhile, pharmacogenetic testing can already help make some UC medications safer.

What did researchers find about mutations in colon cells?

The inner lining of the colon is a single layer of cells arranged in small pits called crypts. Stem cells at the base of each crypt continually produce new lining cells, which repair the damage caused by inflammation. In UC, repeated cycles of damage and repair change which cells survive and spread.

In a 2020 study published in Nature, researchers sequenced the DNA of colon cells from people with UC. They found that the inflamed colon was remodelled by large groups of cells (clones) carrying mutations, most often in the genes NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF. These genes are involved in IL-17 and other inflammatory signals, and the mutations appear to help cells survive in an inflamed environment.

Surprisingly, NFKBIZ mutations were very common in the colon lining of people with UC but rare in colorectal cancer, both in people with UC and in people without it. This suggests that cells with these mutations are less likely to become cancer, and that the mutations that help cells survive inflammation are different from those that drive cancer. These findings may one day lead to new ways to prevent or treat colorectal cancer.

Does ulcerative colitis increase the risk of colorectal cancer?

Yes. In a Scandinavian study of more than 96,000 people with UC followed for up to 49 years, people with UC were 1.66 times more likely to develop colorectal cancer and 1.59 times more likely to die from it than matched people without UC. The good news is that the extra risk has fallen considerably over time, probably because of better treatment and surveillance. The risk is higher in people with UC affecting the whole colon, primary sclerosing cholangitis (a liver condition), onset in childhood or a family history of colorectal cancer. People with long-standing UC usually have regular surveillance colonoscopies, typically starting about eight years after symptoms begin.

How is ulcerative colitis treated today?

Treatment depends on how severe and how extensive the inflammation is. Options include:

• 5-aminosalicylates (5-ASA), such as mesalamine, the first-line treatment for mild to moderate UC.
• Corticosteroids, such as prednisone or budesonide, for short-term control of flares.
• Thiopurines, azathioprine and 6-mercaptopurine, to maintain remission and reduce steroid use.
• Biologics, such as infliximab, adalimumab, vedolizumab, ustekinumab and newer IL-23 blockers, for moderate to severe UC.
• Oral small molecules, such as the JAK inhibitors tofacitinib and upadacitinib, and the S1P receptor modulators ozanimod and etrasimod.
• Cyclosporine or tacrolimus, calcineurin inhibitors sometimes used as rescue therapy for severe UC that does not respond to steroids.

How do genes affect ulcerative colitis medications?

Azathioprine and 6-mercaptopurine: TPMT and NUDT15

The TPMT and NUDT15 enzymes help break down azathioprine and 6-mercaptopurine. People with reduced activity of either enzyme can build up high levels and develop a dangerous drop in white blood cells and other blood cells (myelosuppression). The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends:

• Intermediate metabolizers: start with 30% to 80% of the usual dose, and adjust based on blood counts.
• Poor metabolizers (very low or no activity): for non-cancer conditions such as UC, consider a different immunosuppressant. If a thiopurine is still needed, the dose must be drastically reduced.

TPMT variants are the main cause in people of European and African ancestry, while NUDT15 variants are more common in people of East Asian and Hispanic ancestry. Read more about azathioprine and other long-term immunosuppressants.

Tacrolimus: CYP3A5

Tacrolimus is broken down mainly by CYP3A5 and CYP3A4. Most people of European ancestry do not make the CYP3A5 enzyme, while many people of African ancestry do. People who make CYP3A5 (expressers) clear tacrolimus faster and may take longer to reach the target blood level. The CPIC guideline, developed for transplant patients, recommends a starting dose 1.5 to 2 times higher for expressers, with close monitoring of blood levels.

JAK inhibitors and other medications

Tofacitinib and upadacitinib are broken down mainly by CYP3A4, so medications that strongly block or speed up this enzyme can change their levels. There is no genetic dosing guideline for them. Biologics such as infliximab and vedolizumab are proteins that are not broken down by the liver enzymes on a pharmacogenetic panel. Read more about pharmacogenetic testing and biologics.

People with UC often take other medications too, for example for pain, anxiety, depression or acid reflux, many of which are affected by genes. Read more about which antidepressants can help bowel symptoms.

How can a Pillcheck test help?

Testing TPMT and NUDT15 before starting azathioprine or 6-mercaptopurine is widely recommended. A Pillcheck test reports TPMT, NUDT15, CYP3A5, CYP3A4 and other genes that affect UC medications and many other drugs, such as pain medications, antidepressants and acid reducers. A pharmacist reviews your results together with all your medications and prepares recommendations to share with your gastroenterologist or family doctor.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Summary

• Ulcerative colitis is a chronic inflammatory disease of the colon shaped by genes, gut bacteria and the environment.
• Inflammation in UC selects for colon cells with mutations in inflammatory-signalling genes such as NFKBIZ, which are rarely found in colorectal cancer.
• People with UC have a higher risk of colorectal cancer, although the extra risk has declined, and regular surveillance colonoscopy is recommended.
• Treatment includes 5-ASA, steroids, thiopurines, biologics, JAK inhibitors and S1P modulators.
• TPMT and NUDT15 guide azathioprine and 6-mercaptopurine dosing, and CYP3A5 affects tacrolimus.

Frequently asked questions

Should I have a TPMT test before starting azathioprine?

Yes. Testing TPMT, and ideally NUDT15, before starting azathioprine or 6-mercaptopurine is widely recommended, because it identifies people who need a lower dose or a different medication.

Does ulcerative colitis lead to colon cancer?

UC increases the risk of colorectal cancer, especially when it affects the whole colon or has lasted many years, but most people with UC never develop cancer. Regular surveillance colonoscopy helps find changes early.

Can a genetic test tell me which UC medication will work?

No. There is no genetic test that predicts which UC medication will work best. Pharmacogenetic testing helps with safety and dosing, especially for azathioprine, 6-mercaptopurine and tacrolimus.

Are biologics affected by my genes?

Biologics such as infliximab and vedolizumab are not broken down by the liver enzymes tested in pharmacogenetic panels, so these tests do not guide their dose.

References

Kakiuchi N, Yoshida K, Uchino M, et al. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature. 2020;577(7789):260-265.

Olén O, Erichsen R, Sachs MC, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. 2020;395(10218):123-131.

Raine T, Bonovas S, Burisch J, et al. ECCO guidelines on therapeutics in ulcerative colitis: medical treatment. J Crohns Colitis. 2022;16(1):2-17.

Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019;105(5):1095-1105.

Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther. 2015;98(1):19-24.