Mayo Clinic Researchers Find Genetic Clue to Irritable Bowel Syndrome

[Ecoclimber]

Mayo Clinic Researchers Find Genetic Clue to Irritable Bowel Syndrome

ROCHESTER, Minn. — March 20, 2014 —Is irritable bowel syndrome (IBS) caused by genetics, diet, past trauma, anxiety? All are thought to play a role, but now, for the first time, researchers have reported a defined genetic defect that causes a subset of IBS. The research was published in the journal Gastroenterology.

Researchers estimate that approximately 15 to 20 percent of the Western world has IBS. It is a common disorder that affects the large intestine. Most patients with the disorder commonly experience symptoms of cramping, abdominal pain, bloating gas, diarrhea and constipation. Most treatments for IBS target these symptoms.

Researchers found that patients with a subset of IBS have a specific genetic defect, a mutation of the SCN5A gene. This defect causes patients to have a disruption in bowel function, by affecting the Nav1.5 channel, a sodium channel in the gastrointestinal smooth muscle and pacemaker cells.

The research is in early stages, but the results of this study give researchers hope of finding therapies for these patients.

“This gives us hope that from only treating symptoms of the disease, we can now work to find disease-modifying agents, which is where we really want to be to affect long-term treatment of IBS,” says Gianrico Farrugia, M.D., a study author, Mayo Clinic gastroenterologist and director of the Mayo Clinic Center for Individualized Medicine.

Researchers studied the sodium channel of 584 people with IBS and 1,380 control subjects. The analysis demonstrated that a defect in the SCN5A gene was found in 2.2 percent of IBS patients. The results were confirmed in a genome-wide association study and replicated in 1,745 patients in four independent cohorts of patients with IBS and control subjects.

Additionally, researchers were able to restore function to a patient with constipation predominant IBS with a defective SCN5A gene and resulting abnormally functioning sodium channel. Researchers used a drug called mexiletine, which restored the function of the channel and reversed the patient’s symptoms of constipation and abdominal pain.

This study also included researchers from the Karolinska Institutet in Stockholm, and others in Italy and Greece.

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[Valentijn]

Researchers found that patients with a subset of IBS have a specific genetic defect, a mutation of the SCN5A gene. This defect causes patients to have a disruption in bowel function, by affecting the Nav1.5 channel, a sodium channel in the gastrointestinal smooth muscle and pacemaker cells.

I don't know exactly which SNP they're talking about, but I took a look at the 23andMe data for the entire gene in 12 ME patients I have the data for, compared with 12 controls:

Purple is for genotypes with prevalence of less than 1%, red is 1 - 2.5%, orange is 2.5 - 5%, and yellow is 5-10%. Weighting each color by its rarity (purple = 10, red = 5, orange = 2.5, yellow = 1), the controls score 20 points toward rareness and the ME patents score 62 points. Hence we have a helleva lot more rare results for this gene than the controls do.

I left in some genotypes which had more than 10% prevalence, colored green, which are still over-represented in the ME sample versus the control sample. Missense mutations are in red font, italicized and underlined for the one which has research showing it's likely contributing to disease.

SCN5A can cause long QT disease type 3 in an autosomal dominant manner, meaning that only one copy of a bad allele is needed. No idea if the same gene can cause both dominant and recessive diseases.

 

[Hip]

The Farrugia et al (2014) study in question is this one:

Loss-of-function of the Voltage-gated Sodium Channel NaV1.5 (Channelopathies) in Patients with Irritable Bowel Syndrome

The study concluded that: "About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options."

2% of IBS patients seems like a pretty small IBS subgroup. If you have IBS, it's a 1 in 50 chance you are in this subgroup.

Incidentally, this earlier study by Farrugia et al (2009) concluded that: "the G298S-SCN5A missense mutation caused a marked reduction of whole cell Na+ current and loss of function of Nav1.5, suggesting SCN5A as a candidate gene in the pathophysiology of IBS."

So I am guessing that G298S-SCN5A is the identity of the IBS-associated SCN5A mutation.

I am not sure if this G298S-SCN5A mutation is to be found in the 23andme results.

 

[Valentijn]

I am not sure if this G298S-SCN5A mutation is to be found in the 23andme results.

It's rs137854608 and isn't tested by 23andMe (checked via location on the gene as well, since they like to hide pathogenic SNPs with "i" numbers). Though it's possible that some very rare alleles elsewhere on the gene reflect a mutation on that gene as well. Impossible to verify, unfortunately.