Image: Histopathology showing degranulation of eosinophils (pink) with adjacent nerves (brown) in the duodenum of a patient with functional bowel disorder (Photo courtesy of Dr. Marjorie Walker).
Irritable bowel syndrome (IBS) may be caused by genetics, diet, past trauma, anxiety and all are thought to play a role, but now, for the first time, a defined genetic defect that causes a subset of IBS has been reported.
IBS is a common disorder that affects the large intestine and most patients with the disorder commonly experience symptoms of cramping, abdominal pain, bloating gas, diarrhea and constipation and most treatments for IBS target these symptoms. One of the risk factors for IBS is a family history of the syndrome where those who have a first-degree relative, such as a parent or sibling, with IBS are at increased risk of the condition.
An international team of scientists led by those at the Mayo Clinic (Rochester, MN, USA) studied the sodium channel of people with IBS and control subjects. Many of the patients with cardiac arrhythmias which are caused by mutations in the gene sodium channel, voltage-gated, type V, alpha subunit (SCN5A) also have symptoms of IBS. The team investigated whether patients with IBS have SCN5A variants that affect the function of the sodium ion channel protein Nav1.5.
The investigators performed genotype analysis of SCN5A in 584 persons with IBS and 1,380 control subjects. Mutant forms of SCN5A were expressed in Human Embryonic Kidney (HEK)-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene and replicated in 1,745 patients in four independent cohorts of IBS patients and controls.
Missense mutations were found in SCN5A in 13/584 patients (2.2%). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a significantly greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%). In the GWAS and four replicated studies, the SCN5A locus was strongly associated with IBS.
The scientists were able to restore function to a patient with constipation predominant IBS with a defective SCN5A gene and resulting abnormally functioning sodium channel. They used a drug called mexiletine, which restored the function of the channel and reversed the patient's symptoms of constipation and abdominal pain. Gianrico Farrugia, MD, a lead study author, said, “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.” The study was published on March 5, 2014, in the journal Gastroenterology.