Meeting News

GEM: Family history, microbiome, permeability can stratify high-risk IBD

LAS VEGAS — Looking at people with at least one first-degree relative with Crohn’s allowed researchers to further stratify risk among an already high-risk group, determining certain characteristics that put a person at a five-times greater risk of developing Crohn’s, according to an expert at Crohn’s & Colitis Congress.

“This stratification of a high-risk group gives us insight into how these parameters figure into the pathogenesis of Crohn’s,” Ken Croitoru, MD, of Mount Sinai, said during his presentation.

Croitoru presented preliminary data from the GEM Project, which recruited healthy first-degree relatives of patients with IBD and followed them to look for development of IBD.

The GEM Project recruited 5,085 of these relatives – 69.7% siblings; 30.3% offspring – and collected data on their genetics, environment, diet, microbiome, immune function and intestinal permeability. At the time of recruitment, the subjects did not have any signs of GI disease or distress, Croitoru said.

Those that went on to develop disease became the nested cohort, matched with four healthy controls. The mean time from recruitment to development of disease is about 2.67 years and the study saw 70 occurrences of new-onset Crohn’s disease in the study, 82% of which occurred in siblings.

In looking at this new cohort, Croitoru showed preliminary data that further refined risk among the high-risk group.

First, he showed that patients with more than one first-degree relative with Crohn’s – or multiplex families – were more three times more likely to develop the disease than their monoplex counterparts (HR = 3.17; 95% CI, 1.71-5.85).

“The survival curve significantly split with a hazard ratio of 3 If you come from a very high-risk population to begin with but you are from a multiplex family vs. a monoplex family,” Croitoru said.

Additionally, the GEM Project confirmed that genetic risk score did correlate with disease development with those in the highest risk quartile 2.6 times more likely to develop Crohn’s than the other quartiles (HR = 2.6; 95% CI, 1.25-5.41).

One factor of IBD that the GEM study includes is gut permeability, Croitoru said. He showed permeability data from the first 1,300 patients in which they collected the data and showed that those with abnormal permeability were three times as likely to develop disease (HR = 3.2; 95% CI, 1.73-5.93).

“Permeability has long been discussed as a potential biological marker of risk of developing inflammatory bowel disease. ... What hasn’t been known up until now is whether that abnormal permeability in healthy first-degree relatives actually predicts the likelihood of developing disease,” he said. “This is the first time that abnormal permeability has been shown prospectively to actually associate with future development of inflammatory bowel disease.”

Additionally, Croitoru presented preliminary data on gut diversity and disease risk. He showed that those patients with the lowest diversity were 50% more likely to develop Crohn’s disease than those in the quartile with the most diversity (HR = 0.47; 95% CI, .93-1).

“It has long been said that patients with inflammatory bowel disease have lower diversity. In fact, if we take this diversity index and divide it into four quartiles, we do start to see the association where a lower diversity does associate with a future development of disease,” he said. “Diversity as a lush reflection of the microbiome seems to suggest microbiome may actually associate with your future development of Crohn’s disease.”

With these factors all showing significant risk factors, Croitoru showed how they could be used to create a more accurate risk stratification score to be used among the high-risk population of first-degree relatives of patients with Crohn’s disease.

In the testing set, Croitoru showed that those in the highest decile of risk were five times more likely to develop disease than the others (HR = 4.9; 95% CI, 2.1-11.4).

“In this validation cohort, the risk score that we calculated actually performed very well and, I think, tells us there’s a microbiome signature here that helps differentiate the individuals who go on to develop disease from those that do not go on to develop disease,” Croitoru said. “Now, we are in a position to add to these types of risk score analyses using many of these parameters we are about to embark on. ... The bottom line is, This will help us define who is at high risk within this first-degree relative cohort.” – by Katrina Altersitz

Reference:

Croitoru K. SP87. Presented at: Crohn’s & Colitis Congress; Feb. 7-9, 2019; Las Vegas.

Disclosure: Healio Gastroenterology and Liver Disease could not confirm disclosures at the time of publication.

LAS VEGAS — Looking at people with at least one first-degree relative with Crohn’s allowed researchers to further stratify risk among an already high-risk group, determining certain characteristics that put a person at a five-times greater risk of developing Crohn’s, according to an expert at Crohn’s & Colitis Congress.

“This stratification of a high-risk group gives us insight into how these parameters figure into the pathogenesis of Crohn’s,” Ken Croitoru, MD, of Mount Sinai, said during his presentation.

Croitoru presented preliminary data from the GEM Project, which recruited healthy first-degree relatives of patients with IBD and followed them to look for development of IBD.

The GEM Project recruited 5,085 of these relatives – 69.7% siblings; 30.3% offspring – and collected data on their genetics, environment, diet, microbiome, immune function and intestinal permeability. At the time of recruitment, the subjects did not have any signs of GI disease or distress, Croitoru said.

Those that went on to develop disease became the nested cohort, matched with four healthy controls. The mean time from recruitment to development of disease is about 2.67 years and the study saw 70 occurrences of new-onset Crohn’s disease in the study, 82% of which occurred in siblings.

In looking at this new cohort, Croitoru showed preliminary data that further refined risk among the high-risk group.

First, he showed that patients with more than one first-degree relative with Crohn’s – or multiplex families – were more three times more likely to develop the disease than their monoplex counterparts (HR = 3.17; 95% CI, 1.71-5.85).

“The survival curve significantly split with a hazard ratio of 3 If you come from a very high-risk population to begin with but you are from a multiplex family vs. a monoplex family,” Croitoru said.

Additionally, the GEM Project confirmed that genetic risk score did correlate with disease development with those in the highest risk quartile 2.6 times more likely to develop Crohn’s than the other quartiles (HR = 2.6; 95% CI, 1.25-5.41).

One factor of IBD that the GEM study includes is gut permeability, Croitoru said. He showed permeability data from the first 1,300 patients in which they collected the data and showed that those with abnormal permeability were three times as likely to develop disease (HR = 3.2; 95% CI, 1.73-5.93).

“Permeability has long been discussed as a potential biological marker of risk of developing inflammatory bowel disease. ... What hasn’t been known up until now is whether that abnormal permeability in healthy first-degree relatives actually predicts the likelihood of developing disease,” he said. “This is the first time that abnormal permeability has been shown prospectively to actually associate with future development of inflammatory bowel disease.”

PAGE BREAK

Additionally, Croitoru presented preliminary data on gut diversity and disease risk. He showed that those patients with the lowest diversity were 50% more likely to develop Crohn’s disease than those in the quartile with the most diversity (HR = 0.47; 95% CI, .93-1).

“It has long been said that patients with inflammatory bowel disease have lower diversity. In fact, if we take this diversity index and divide it into four quartiles, we do start to see the association where a lower diversity does associate with a future development of disease,” he said. “Diversity as a lush reflection of the microbiome seems to suggest microbiome may actually associate with your future development of Crohn’s disease.”

With these factors all showing significant risk factors, Croitoru showed how they could be used to create a more accurate risk stratification score to be used among the high-risk population of first-degree relatives of patients with Crohn’s disease.

In the testing set, Croitoru showed that those in the highest decile of risk were five times more likely to develop disease than the others (HR = 4.9; 95% CI, 2.1-11.4).

“In this validation cohort, the risk score that we calculated actually performed very well and, I think, tells us there’s a microbiome signature here that helps differentiate the individuals who go on to develop disease from those that do not go on to develop disease,” Croitoru said. “Now, we are in a position to add to these types of risk score analyses using many of these parameters we are about to embark on. ... The bottom line is, This will help us define who is at high risk within this first-degree relative cohort.” – by Katrina Altersitz

Reference:

Croitoru K. SP87. Presented at: Crohn’s & Colitis Congress; Feb. 7-9, 2019; Las Vegas.

Disclosure: Healio Gastroenterology and Liver Disease could not confirm disclosures at the time of publication.

    See more from Crohns & Colitis Congress