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Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.

https://arctichealth.org/en/permalink/ahliterature107038
Source
PLoS Genet. 2013;9(9):e1003723
Publication Type
Article
Date
2013
Author
Mélissa Beaudoin
Philippe Goyette
Gabrielle Boucher
Ken Sin Lo
Manuel A Rivas
Christine Stevens
Azadeh Alikashani
Martin Ladouceur
David Ellinghaus
Leif Törkvist
Gautam Goel
Caroline Lagacé
Vito Annese
Alain Bitton
Jakob Begun
Steve R Brant
Francesca Bresso
Judy H Cho
Richard H Duerr
Jonas Halfvarson
Dermot P B McGovern
Graham Radford-Smith
Stefan Schreiber
Philip L Schumm
Yashoda Sharma
Mark S Silverberg
Rinse K Weersma
Mauro D'Amato
Severine Vermeire
Andre Franke
Guillaume Lettre
Ramnik J Xavier
Mark J Daly
John D Rioux
Author Affiliation
Montreal Heart Institute, Research Center, Montreal, Quebec, Canada.
Source
PLoS Genet. 2013;9(9):e1003723
Date
2013
Language
English
Publication Type
Article
Keywords
CARD Signaling Adaptor Proteins - genetics
Canada
Colitis, Ulcerative - genetics - pathology
Crohn Disease - genetics - pathology
Ethnic Groups
Genetic Predisposition to Disease
Genome-Wide Association Study
High-Throughput Nucleotide Sequencing
Humans
Polymorphism, Single Nucleotide
Receptors, Interleukin - genetics
Ubiquitin-Protein Ligases - genetics
Abstract
Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.
Notes
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PubMed ID
24068945 View in PubMed
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IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease.

https://arctichealth.org/en/permalink/ahliterature152922
Source
BMC Med Genet. 2009;10:8
Publication Type
Article
Date
2009
Author
Elisabet Einarsdottir
Lotta L E Koskinen
Emma Dukes
Kati Kainu
Sari Suomela
Maarit Lappalainen
Fabiana Ziberna
Ilma R Korponay-Szabo
Kalle Kurppa
Katri Kaukinen
Róza Adány
Zsuzsa Pocsai
György Széles
Martti Färkkilä
Ulla Turunen
Leena Halme
Paulina Paavola-Sakki
Tarcisio Not
Serena Vatta
Alessandro Ventura
Robert Löfberg
Leif Torkvist
Francesca Bresso
Jonas Halfvarson
Markku Mäki
Kimmo Kontula
Ulpu Saarialho-Kere
Juha Kere
Mauro D'Amato
Päivi Saavalainen
Author Affiliation
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. elisabet.einarsdottir@helsinki.fi
Source
BMC Med Genet. 2009;10:8
Date
2009
Language
English
Publication Type
Article
Keywords
Case-Control Studies
Celiac Disease - complications - genetics
Colitis, Ulcerative - complications - genetics
Crohn Disease - complications - genetics
Finland
Genetic markers
Genetic Predisposition to Disease
Genotype
Haplotypes
Humans
Hungary
Italy
Linkage Disequilibrium
Psoriasis - complications - genetics
Receptors, Interleukin - genetics
Sweden
Abstract
Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases.
We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease.
Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples.
Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.
Notes
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PubMed ID
19175939 View in PubMed
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PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.

https://arctichealth.org/en/permalink/ahliterature150812
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Publication Type
Article
Date
Oct-2009
Author
Marco Zucchelli
Leif Torkvist
Francesca Bresso
Jonas Halfvarson
Anna Hellquist
Francesca Anedda
Ghazaleh Assadi
Gunnar B Lindgren
Monika Svanfeldt
Martin Janson
Colin L Noble
Sven Pettersson
Maarit Lappalainen
Paulina Paavola-Sakki
Leena Halme
Martti Färkkilä
Ulla Turunen
Jack Satsangi
Kimmo Kontula
Robert Löfberg
Juha Kere
Mauro D'Amato
Author Affiliation
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Date
Oct-2009
Language
English
Publication Type
Article
Keywords
Adult
Case-Control Studies
Cohort Studies
Colitis, Ulcerative - genetics
Crohn Disease - genetics
Female
Finland
Genotype
Humans
Male
Middle Aged
NF-kappa B - genetics - metabolism
Nod2 Signaling Adaptor Protein - genetics - metabolism
Polymorphism, Single Nucleotide - genetics
Sweden
Symporters - genetics
Abstract
Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF-kappaB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD.
Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2-mediated activation of NF-kappaB.
The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval [CI] 1.34-2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44-0.90). The PepT1 variant encoded by the C allele (PepT1-Ser117) was associated with reduced signaling downstream of NOD2 (P
PubMed ID
19462432 View in PubMed
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Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease.

https://arctichealth.org/en/permalink/ahliterature165784
Source
Inflamm Bowel Dis. 2007 May;13(5):531-6
Publication Type
Article
Date
May-2007
Author
Francesca Bresso
Johan Askling
Marco Astegiano
Brunello Demarchi
Nicoletta Sapone
Mario Rizzetto
Paolo Gionchetti
Karen M Lammers
Annalisa de Leone
Gabriele Riegler
Elaine R Nimmo
Hazel Drummond
Colin Noble
Leif Torkvist
Anders Ekbom
Marco Zucchelli
Robert Lofberg
Jack Satsangi
Sven Pettersson
Mauro D'Amato
Author Affiliation
Strategic Research Center IRIS, Karolinska Institutet, Stockholm, Sweden.
Source
Inflamm Bowel Dis. 2007 May;13(5):531-6
Date
May-2007
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Crohn Disease - genetics - pathology - physiopathology
Cystic Fibrosis Transmembrane Conductance Regulator - genetics - physiology
Female
Genetic Predisposition to Disease
Genotype
Heterozygote Detection
Humans
Italy
Male
Middle Aged
Mutation
Phenotype
Scotland
Sweden
Abstract
Inflammatory bowel disease (IBD) is an epithelial barrier disease that is thought to result from a dysregulated interaction with bacteria in the intestine of genetically predisposed individuals. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in the autosomal recessive disease cystic fibrosis, modulates gut permeability, mucus production, and epithelial interactions with bacteria. The cystic fibrosis DeltaF508 mutation is commonly found in the general population and has been shown to result in a reduced number of CFTR molecules at the surface of epithelial cells. Given the important biological functions of CFTR in the intestine, we tested whether this mutation is of relevance to IBD.
Using DNA heteroduplex analysis, we investigated the distribution of DeltaF508 heterozygosity in 2568 subjects from three independent cohorts of Italian, Swedish, and Scottish IBD patients and controls.
In all three cohorts an association between DeltaF508 and Crohn's disease (CD) was observed. Specifically, DeltaF508 heterozygosity was markedly underrepresented in CD patients from Italy and Sweden (P = 0.021 and 0.027 versus controls, respectively), while stratification for disease location revealed an absence of DeltaF508 carriers among Scottish CD patients with right-sided colitis (P = 0.023 versus all other locations).
DeltaF508 heterozygosity might exert a protective effect in CD.
PubMed ID
17206681 View in PubMed
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