In brief:
"An international team of researchers has identified four genetic variants common to celiac disease and Crohn’s disease.
The research may help to explain why people who have celiac disease appear to have a higher rate of Crohn’s disease than the general population. It may one day lead to new treatments that address the underlying inflammation involved in both conditions.
The new study made use of a new way to analyze hundreds of thousands of genetic variations, called single nucleotide polymorphisms, or SNPs, that may be involved in any one disease, called a genome-wide association study, or GWAS.
“It’s completely changed the way we can identify genetic risk factors,” says study co-author John D. Rioux, PhD, an associate professor of medicine at the University of Montreal, in Quebec, Canada.
“There are sequence differences at the genetic level that get translated down to the protein levels,” Rioux says. “And these differences may really nudge a person toward inflammation and we’re just in the beginning, but we hope they may elucidate a common pathway and one day help us discover treatments that correct the underlying genetic changes.”
Looking for Genes That Regulate Intestinal Inflammation
For the study, which is published in the Jan. 27 issue of PLoS Genetics, researchers compared 471,504 SNPs, representing the genomes of about 10,000 people, some of whom had Crohn’s disease, some who had celiac disease, and some healthy people.
They found four genes that appeared to contribute to the risk for both diseases.
Two of these genes, IL18RAP and PTPN2, had previously been reported to be associated with each disease.
Another, called TAGAP, had previously been identified as an area of risk in celiac disease but was new to Crohn’s disease risk.
The fourth, PUS10, had been previously been tied to Crohn’s disease, celiac disease, and ulcerative colitis.
Three of the four appear to be involved in controlling how the immune system responds to perceived threats.
“The first three we can say are involved in T-lymphocyte function,” Rioux says. “They seem to have a role to play in how these cells respond to a given stimulus.”
Rioux says that having your immune system respond to incoming threats is a good thing, but sometimes the body goes overboard, attacking itself instead of a foreign invader, and that overstimulation can contribute to host of diseases, including type 1 diabetes, rheumatoid arthritis, lupus, and many others.
Links Between Celiac and Crohn’s Disease
Celiac disease (also called celiac sprue) is an autoimmune disease where the lining of the intestine becomes damaged by a reaction from eating gluten, a protein that’s found in wheat and other grains like rye and barley.
The damage prevents the intestine from absorbing nutrients in food, which can cause problems ranging from anemia to osteoporosis to lactose intolerance. Celiac disease has been linked to a higher risk for intestinal cancers.
In Crohn’s disease, inflammation of the digestive tract can cause the bowel to empty frequently, resulting in diarrhea.
THE FULL ARTICLE
Some research has shown that people with one condition are more prone to the other. One study, for example, found that more than 18.5% of patients with Crohn’s disease also have celiac disease."
A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease
Eleonora A. M. Festen1,2#, Philippe Goyette3#, Todd Green4#, Gabrielle Boucher3, Claudine Beauchamp3, Gosia Trynka2, Patrick C. Dubois5, Caroline Lagacé3, Pieter C. F. Stokkers6, Daan W. Hommes7, Donatella Barisani8, Orazio Palmieri9, Vito Annese9, David A. van Heel5, Rinse K. Weersma1¶*, Mark J. Daly4,10¶, Cisca Wijmenga2¶, John D. Rioux3¶*
1 Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands, 2 Department of Genetics, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands, 3 Research Center, Université de Montréal and the Montreal Heart Institute, Montreal, Quebec, Canada, 4 The Broad Institute, Cambridge, Massachusetts, United States of America, 5 Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 6 Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands, 7 Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands, 8 Department of Experimental Medicine, Faculty of Medicine, University of Milano-Bicocca, Monza, Italy, 9 U. O. Gastroenterologia ed Endoscopia Digestiva, Ospedale “Casa Sollievo della Sofferenza”, IRCCS, San Giovanni Rotondo, Italy, 10 Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract Top
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.
"An international team of researchers has identified four genetic variants common to celiac disease and Crohn’s disease.
The research may help to explain why people who have celiac disease appear to have a higher rate of Crohn’s disease than the general population. It may one day lead to new treatments that address the underlying inflammation involved in both conditions.
The new study made use of a new way to analyze hundreds of thousands of genetic variations, called single nucleotide polymorphisms, or SNPs, that may be involved in any one disease, called a genome-wide association study, or GWAS.
“It’s completely changed the way we can identify genetic risk factors,” says study co-author John D. Rioux, PhD, an associate professor of medicine at the University of Montreal, in Quebec, Canada.
“There are sequence differences at the genetic level that get translated down to the protein levels,” Rioux says. “And these differences may really nudge a person toward inflammation and we’re just in the beginning, but we hope they may elucidate a common pathway and one day help us discover treatments that correct the underlying genetic changes.”
Looking for Genes That Regulate Intestinal Inflammation
For the study, which is published in the Jan. 27 issue of PLoS Genetics, researchers compared 471,504 SNPs, representing the genomes of about 10,000 people, some of whom had Crohn’s disease, some who had celiac disease, and some healthy people.
They found four genes that appeared to contribute to the risk for both diseases.
Two of these genes, IL18RAP and PTPN2, had previously been reported to be associated with each disease.
Another, called TAGAP, had previously been identified as an area of risk in celiac disease but was new to Crohn’s disease risk.
The fourth, PUS10, had been previously been tied to Crohn’s disease, celiac disease, and ulcerative colitis.
Three of the four appear to be involved in controlling how the immune system responds to perceived threats.
“The first three we can say are involved in T-lymphocyte function,” Rioux says. “They seem to have a role to play in how these cells respond to a given stimulus.”
Rioux says that having your immune system respond to incoming threats is a good thing, but sometimes the body goes overboard, attacking itself instead of a foreign invader, and that overstimulation can contribute to host of diseases, including type 1 diabetes, rheumatoid arthritis, lupus, and many others.
Links Between Celiac and Crohn’s Disease
Celiac disease (also called celiac sprue) is an autoimmune disease where the lining of the intestine becomes damaged by a reaction from eating gluten, a protein that’s found in wheat and other grains like rye and barley.
The damage prevents the intestine from absorbing nutrients in food, which can cause problems ranging from anemia to osteoporosis to lactose intolerance. Celiac disease has been linked to a higher risk for intestinal cancers.
In Crohn’s disease, inflammation of the digestive tract can cause the bowel to empty frequently, resulting in diarrhea.
THE FULL ARTICLE
Some research has shown that people with one condition are more prone to the other. One study, for example, found that more than 18.5% of patients with Crohn’s disease also have celiac disease."
A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease
Eleonora A. M. Festen1,2#, Philippe Goyette3#, Todd Green4#, Gabrielle Boucher3, Claudine Beauchamp3, Gosia Trynka2, Patrick C. Dubois5, Caroline Lagacé3, Pieter C. F. Stokkers6, Daan W. Hommes7, Donatella Barisani8, Orazio Palmieri9, Vito Annese9, David A. van Heel5, Rinse K. Weersma1¶*, Mark J. Daly4,10¶, Cisca Wijmenga2¶, John D. Rioux3¶*
1 Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands, 2 Department of Genetics, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands, 3 Research Center, Université de Montréal and the Montreal Heart Institute, Montreal, Quebec, Canada, 4 The Broad Institute, Cambridge, Massachusetts, United States of America, 5 Centre for Digestive Diseases, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 6 Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands, 7 Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands, 8 Department of Experimental Medicine, Faculty of Medicine, University of Milano-Bicocca, Monza, Italy, 9 U. O. Gastroenterologia ed Endoscopia Digestiva, Ospedale “Casa Sollievo della Sofferenza”, IRCCS, San Giovanni Rotondo, Italy, 10 Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract Top
Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.
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