Progress Made on Genetic Profile for Ulcerative Colitis

NEW ORLEANS — More than 50 genetic risk factors for ulcerative colitis have now been identified by the International Inflammatory Bowel Disease Genetics Consortium, said John D. Rioux, Ph.D.

“The work of the International IBD Consortium has dramatically increased the number of known UC [ulcerative colitis] loci and is expected to significantly increase our understanding of disease pathogenesis that relates to both shared and UC-specific inflammatory pathways,” said Dr. Rioux of the University of Montreal. The Consortium spans 15 countries and employs over 80 clinical and basic researchers.

Genome-wide association (GWA) studies analyze “hundreds of thousands of genetic variants for thousands of patients and controls” to identify genetic risk factors, he said.

GWA studies have identified genetic risk factors for Crohn's disease.

While individual studies have been successful, the statistical power for gene discovery is limited by sample size.

The larger the sample size, the greater the number of genetic risk factors identified, he noted.

Previously, the Consortium performed one of the first studies to combine GWA results, and identified more than 30 risk factors for Crohn's disease.

“At that time, much less was known about the genetics of UC, with only the MHC and the IL23R gene having confirmed associations.

In the last year, multiple GWAs of UC have been done and have produced 18 independent new associations.

“These studies provided a unique opportunity to identify a much more complete catalog of genetic risk factors,” he said.

In the current study, results from six GWA studies of UC were combined in a meta-analysis.

Data from 6,433 patients with UC and 20,999 population controls from North America and Europe were combined into a dataset.

“Out of nearly millions of polymorphisms examined,” the tests ultimately revealed 75 independent genomic regions significantly associated with UC.

In preliminary investigations, the meta-analysis has confirmed 18 known UC loci, 21 novel loci, and 4 nominally significant loci (which investigators expect to become significant upon further analyses), for a total of 43 genetic risk factors to date.

Another 26 genetic risk factors are being studied but have not yet been replicated.

“Many of the UC genetic risk factors are shared with Crohn's disease—nearly 50%—as well as other inflammatory diseases,” he noted.

The other inflammatory diseases include psoriasis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and others.

“We predict there are at least 52 loci associated with UC, about 50% of which are shared with Crohn's disease and about 25% with other inflammatory diagnoses.

“The remainder appear to be UC-specific,” he said.

“The research into the genetics of ulcerative colitis has highlighted the similarities and differences between ulcerative colitis and Crohn's disease, said Dr. María T. Abreu in an interview.

“It shows us some of the explanations for why patients with ulcerative colitis who have a J-pouch [also called an ileal pouch–anal anastomosis] may ultimately develop Crohn's disease,” said Dr. Abreu, professor of medicine and chief, division of gastroenterology, University of Miami.

The Consortium is currently testing all novel loci in an independent set of 10,000 UC patients and a similar number of population controls to confirm these findings, but even the preliminary results provide “convincing evidence,” he said, of associations to genes of biological significance to disease pathogenesis: TNFRSF14, JAK2, CARD9 and others.

An analysis of the literature suggests that novel UC genes pinpoint potential molecular mechanisms.

“In other words, each new UC gene contributes to the puzzle,” he said.

For example, ETS1 on chromosome 11 has a profound impact on Th1 immune responses. DAP (death-associated protein) on chromosome 5 modulates mTOR (mammalian target of rapamycin) activity. WSB1 on chromosome 17 is a hedgehog-inducible ubiquitin ligase, and its loss results in spontaneous intestinal inflammation.

“We can begin to put these into biological pathways.

Many genes in these pathways protect or predispose to disease and we can identify novel targets and appropriate genetic testing within the context of clinical trials and patient selection,” he said.

“Our work,” he added, “has just begun.”

'We predict there are at least 52 loci associated with UC.'

Source DR. RIOUX

NEW ORLEANS — More than 50 genetic risk factors for ulcerative colitis have now been identified by the International Inflammatory Bowel Disease Genetics Consortium, said John D. Rioux, Ph.D.

“The work of the International IBD Consortium has dramatically increased the number of known UC [ulcerative colitis] loci and is expected to significantly increase our understanding of disease pathogenesis that relates to both shared and UC-specific inflammatory pathways,” said Dr. Rioux of the University of Montreal. The Consortium spans 15 countries and employs over 80 clinical and basic researchers.

Genome-wide association (GWA) studies analyze “hundreds of thousands of genetic variants for thousands of patients and controls” to identify genetic risk factors, he said.

GWA studies have identified genetic risk factors for Crohn's disease.

While individual studies have been successful, the statistical power for gene discovery is limited by sample size.

The larger the sample size, the greater the number of genetic risk factors identified, he noted.

Previously, the Consortium performed one of the first studies to combine GWA results, and identified more than 30 risk factors for Crohn's disease.

“At that time, much less was known about the genetics of UC, with only the MHC and the IL23R gene having confirmed associations.

In the last year, multiple GWAs of UC have been done and have produced 18 independent new associations.

“These studies provided a unique opportunity to identify a much more complete catalog of genetic risk factors,” he said.

In the current study, results from six GWA studies of UC were combined in a meta-analysis.

Data from 6,433 patients with UC and 20,999 population controls from North America and Europe were combined into a dataset.

“Out of nearly millions of polymorphisms examined,” the tests ultimately revealed 75 independent genomic regions significantly associated with UC.

In preliminary investigations, the meta-analysis has confirmed 18 known UC loci, 21 novel loci, and 4 nominally significant loci (which investigators expect to become significant upon further analyses), for a total of 43 genetic risk factors to date.

Another 26 genetic risk factors are being studied but have not yet been replicated.

“Many of the UC genetic risk factors are shared with Crohn's disease—nearly 50%—as well as other inflammatory diseases,” he noted.

The other inflammatory diseases include psoriasis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and others.

“We predict there are at least 52 loci associated with UC, about 50% of which are shared with Crohn's disease and about 25% with other inflammatory diagnoses.

“The remainder appear to be UC-specific,” he said.

“The research into the genetics of ulcerative colitis has highlighted the similarities and differences between ulcerative colitis and Crohn's disease, said Dr. María T. Abreu in an interview.

“It shows us some of the explanations for why patients with ulcerative colitis who have a J-pouch [also called an ileal pouch–anal anastomosis] may ultimately develop Crohn's disease,” said Dr. Abreu, professor of medicine and chief, division of gastroenterology, University of Miami.

The Consortium is currently testing all novel loci in an independent set of 10,000 UC patients and a similar number of population controls to confirm these findings, but even the preliminary results provide “convincing evidence,” he said, of associations to genes of biological significance to disease pathogenesis: TNFRSF14, JAK2, CARD9 and others.

An analysis of the literature suggests that novel UC genes pinpoint potential molecular mechanisms.

“In other words, each new UC gene contributes to the puzzle,” he said.

For example, ETS1 on chromosome 11 has a profound impact on Th1 immune responses. DAP (death-associated protein) on chromosome 5 modulates mTOR (mammalian target of rapamycin) activity. WSB1 on chromosome 17 is a hedgehog-inducible ubiquitin ligase, and its loss results in spontaneous intestinal inflammation.

“We can begin to put these into biological pathways.

Many genes in these pathways protect or predispose to disease and we can identify novel targets and appropriate genetic testing within the context of clinical trials and patient selection,” he said.

“Our work,” he added, “has just begun.”

'We predict there are at least 52 loci associated with UC.'

Source DR. RIOUX

NEW ORLEANS — More than 50 genetic risk factors for ulcerative colitis have now been identified by the International Inflammatory Bowel Disease Genetics Consortium, said John D. Rioux, Ph.D.

“The work of the International IBD Consortium has dramatically increased the number of known UC [ulcerative colitis] loci and is expected to significantly increase our understanding of disease pathogenesis that relates to both shared and UC-specific inflammatory pathways,” said Dr. Rioux of the University of Montreal. The Consortium spans 15 countries and employs over 80 clinical and basic researchers.

Genome-wide association (GWA) studies analyze “hundreds of thousands of genetic variants for thousands of patients and controls” to identify genetic risk factors, he said.

GWA studies have identified genetic risk factors for Crohn's disease.

While individual studies have been successful, the statistical power for gene discovery is limited by sample size.

The larger the sample size, the greater the number of genetic risk factors identified, he noted.

Previously, the Consortium performed one of the first studies to combine GWA results, and identified more than 30 risk factors for Crohn's disease.

“At that time, much less was known about the genetics of UC, with only the MHC and the IL23R gene having confirmed associations.

In the last year, multiple GWAs of UC have been done and have produced 18 independent new associations.

“These studies provided a unique opportunity to identify a much more complete catalog of genetic risk factors,” he said.

In the current study, results from six GWA studies of UC were combined in a meta-analysis.

Data from 6,433 patients with UC and 20,999 population controls from North America and Europe were combined into a dataset.

“Out of nearly millions of polymorphisms examined,” the tests ultimately revealed 75 independent genomic regions significantly associated with UC.

In preliminary investigations, the meta-analysis has confirmed 18 known UC loci, 21 novel loci, and 4 nominally significant loci (which investigators expect to become significant upon further analyses), for a total of 43 genetic risk factors to date.

Another 26 genetic risk factors are being studied but have not yet been replicated.

“Many of the UC genetic risk factors are shared with Crohn's disease—nearly 50%—as well as other inflammatory diseases,” he noted.

The other inflammatory diseases include psoriasis, celiac disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, and others.

“We predict there are at least 52 loci associated with UC, about 50% of which are shared with Crohn's disease and about 25% with other inflammatory diagnoses.

“The remainder appear to be UC-specific,” he said.

“The research into the genetics of ulcerative colitis has highlighted the similarities and differences between ulcerative colitis and Crohn's disease, said Dr. María T. Abreu in an interview.

“It shows us some of the explanations for why patients with ulcerative colitis who have a J-pouch [also called an ileal pouch–anal anastomosis] may ultimately develop Crohn's disease,” said Dr. Abreu, professor of medicine and chief, division of gastroenterology, University of Miami.

The Consortium is currently testing all novel loci in an independent set of 10,000 UC patients and a similar number of population controls to confirm these findings, but even the preliminary results provide “convincing evidence,” he said, of associations to genes of biological significance to disease pathogenesis: TNFRSF14, JAK2, CARD9 and others.

An analysis of the literature suggests that novel UC genes pinpoint potential molecular mechanisms.

“In other words, each new UC gene contributes to the puzzle,” he said.

For example, ETS1 on chromosome 11 has a profound impact on Th1 immune responses. DAP (death-associated protein) on chromosome 5 modulates mTOR (mammalian target of rapamycin) activity. WSB1 on chromosome 17 is a hedgehog-inducible ubiquitin ligase, and its loss results in spontaneous intestinal inflammation.

“We can begin to put these into biological pathways.

Many genes in these pathways protect or predispose to disease and we can identify novel targets and appropriate genetic testing within the context of clinical trials and patient selection,” he said.

“Our work,” he added, “has just begun.”

'We predict there are at least 52 loci associated with UC.'

Source DR. RIOUX