Understanding Inflammatory Bowel Diseases: Genetics Are Key

Genetic information may help develop treatment guidelines for Crohn’s disease and ulcerative colitis.

A new understanding of inflammatory bowel diseases recently emerged following an analysis of genetic and clinical data from more than 30,000 patients.

A study showed that genetic factors can affect the location of inflammation in the gut, with serious implications for diagnosis and treatment of patients. As the largest study of its kind, this research reveals a continuum of inflammatory bowel diseases, showing that genetic information could be used to uncover misdiagnoses.

The research demonstrates the need for worldwide clinical collaborations using information about symptoms to better comprehend the genetics of complex diseases, according to the study. Inflammatory bowel disease (IBD) refers to 2 related immune diseases: Crohn’s disease and ulcerative colitis.

However, the study shows that a binary diagnosis of the disease is oversimplified. According to genetic data, IBD is a complex continuum of disorders that largely depend on the site of inflammation.

It has long been known that disease location in Crohn’s disease is important, but the new observation that large bowel Crohn’s disease is half-way between ulcerative colitis and small bowel Crohn’s disease on this genetic spectrum suggests that important aspects of disease biology are associated with location.

“Patients who initially present with similar IBD symptoms progress in drastically different ways. Some experience a mild course of disease while others need invasive surgery,” said study first author Dr. Isabelle Cleynen, of the Wellcome Trust Sanger Institute and KU Leuven. “Our current symptom-led system of classification doesn’t clearly predict which path a particular patient is likely to take. Our genetic data reflect this same uncertainty.”

Prior research found that genes involved in IBD are largely shared between Crohn’s disease and ulcerative colitis, with only a small number of genes unique to each disease. The new study combined the genetic information with clinical symptoms to create an understanding of the biology behind the disease.

Diagnosis is based on clinical evidence and symptoms, with different medication and surgery indicated for Crohn’s disease and ulcerative colitis. Clinicians can find it difficult to diagnose some patients who present with either disease due to the similarity between these conditions.

The genetic continuum between both ends of the spectrum explains some of the difficulty in diagnosis, which suggests patients may benefit from reclassification.

At either end of the spectrum, genetic markers may have some diagnostic utility. Physicians reevaluated the records of outlier patients with genetic factors that strongly indicated Crohn’s disease, but had been originally diagnosed with ulcerative colitis or the other way around.

Findings showed that doctors had raised doubts about the diagnosis 3 times more often than for randomly chosen patients.

“For a small subset of patients, genetics can uncover a misdiagnosis. Working with clinicians we hope this will help prevent costly and traumatic unnecessary surgery,” said corresponding author Dr. Jeffrey Barrett, of the Wellcome Trust Sanger Institute and director of the Centre for Therapeutic Target Validation. “However, in the vast majority of cases, the genetic scores we’ve identified for each condition are not different enough to be used diagnostically. Further research pairing genetic data with patient responses to treatment over time will help us to better understand what’s happening on a molecular level in patients with different forms of IBD.”

Genetic information could be used to develop treatment guidelines or determine which patients to include in a clinical trial to obtain the best results. Genetics could also be used as another piece of evidence to catch rare mistakes in diagnosis and to prevent unnecessary surgery.

“In order to personalize treatments, we need to be open-minded about the clinical categories we have constructed by observing symptoms in isolation,” said corresponding author Dr. Charlie Lees, consultant gastroenterologist and senior lecturer at the University of Edinburgh. “It is crucial that clinicians and researchers continue to work closely together and to share comprehensive data that will help to solve this complex puzzle.”