Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

Pankaj Yadav, David Ellinghaus, Gaëlle Rémy, Sandra Freitag-Wolf, Anabelle Cesaro, Frauke Degenhardt, Gabrielle Boucher, Myriam Delacre, Laurent Peyrin-Biroulet, Muriel Pichavant, John D Rioux, Philippe Gosset, Andre Franke, L Philip Schumm, Michael Krawczak, Mathias Chamaillard, Astrid Dempfle, Vibeke Andersen, International IBD Genetics Consortium

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BACKGROUND & AIMS: The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene-smoking interactions) that affect risk for Crohn's disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD.

METHODS: We used 55 Immunochip-wide datasets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10(-/-) and Nod2(-/-) mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction.

RESULTS: We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P < 5.0 × 10(-5); heterogeneity Cochrane Q test P > .05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of Interleukin 10 (il10)-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke.

CONCLUSIONS: In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene-smoking interactions were confirmed in mice with disruption of Il10 and Nod2-variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.

OriginalsprogEngelsk
TidsskriftGastroenterology
Vol/bind153
Udgave nummer2
Sider (fra-til)550-565
ISSN0016-5085
DOI
StatusUdgivet - aug. 2017

Fingeraftryk

Inflammatory Bowel Diseases
Smoke
Smoking
Crohn Disease
Single Nucleotide Polymorphism
Ulcerative Colitis
Interleukin-10
Interferon-gamma
Meta-Analysis
Ileitis
Colitis
Small Intestine
Intestines
Alleles

Citer dette

Yadav, P., Ellinghaus, D., Rémy, G., Freitag-Wolf, S., Cesaro, A., Degenhardt, F., ... International IBD Genetics Consortium (2017). Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice. Gastroenterology, 153(2), 550-565. https://doi.org/10.1053/j.gastro.2017.05.010
Yadav, Pankaj ; Ellinghaus, David ; Rémy, Gaëlle ; Freitag-Wolf, Sandra ; Cesaro, Anabelle ; Degenhardt, Frauke ; Boucher, Gabrielle ; Delacre, Myriam ; Peyrin-Biroulet, Laurent ; Pichavant, Muriel ; Rioux, John D ; Gosset, Philippe ; Franke, Andre ; Schumm, L Philip ; Krawczak, Michael ; Chamaillard, Mathias ; Dempfle, Astrid ; Andersen, Vibeke ; International IBD Genetics Consortium. / Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice. I: Gastroenterology. 2017 ; Bind 153, Nr. 2. s. 550-565.
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title = "Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice",
abstract = "BACKGROUND & AIMS: The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene-smoking interactions) that affect risk for Crohn's disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD.METHODS: We used 55 Immunochip-wide datasets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10(-/-) and Nod2(-/-) mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction.RESULTS: We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P < 5.0 × 10(-5); heterogeneity Cochrane Q test P > .05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45{\%} of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of Interleukin 10 (il10)-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke.CONCLUSIONS: In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene-smoking interactions were confirmed in mice with disruption of Il10 and Nod2-variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.",
keywords = "Journal Article",
author = "Pankaj Yadav and David Ellinghaus and Ga{\"e}lle R{\'e}my and Sandra Freitag-Wolf and Anabelle Cesaro and Frauke Degenhardt and Gabrielle Boucher and Myriam Delacre and Laurent Peyrin-Biroulet and Muriel Pichavant and Rioux, {John D} and Philippe Gosset and Andre Franke and Schumm, {L Philip} and Michael Krawczak and Mathias Chamaillard and Astrid Dempfle and Vibeke Andersen and {International IBD Genetics Consortium}",
note = "Copyright {\circledC} 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2017",
month = "8",
doi = "10.1053/j.gastro.2017.05.010",
language = "English",
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Yadav, P, Ellinghaus, D, Rémy, G, Freitag-Wolf, S, Cesaro, A, Degenhardt, F, Boucher, G, Delacre, M, Peyrin-Biroulet, L, Pichavant, M, Rioux, JD, Gosset, P, Franke, A, Schumm, LP, Krawczak, M, Chamaillard, M, Dempfle, A, Andersen, V & International IBD Genetics Consortium 2017, 'Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice', Gastroenterology, bind 153, nr. 2, s. 550-565. https://doi.org/10.1053/j.gastro.2017.05.010

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice. / Yadav, Pankaj; Ellinghaus, David; Rémy, Gaëlle; Freitag-Wolf, Sandra; Cesaro, Anabelle; Degenhardt, Frauke; Boucher, Gabrielle; Delacre, Myriam; Peyrin-Biroulet, Laurent; Pichavant, Muriel; Rioux, John D; Gosset, Philippe; Franke, Andre; Schumm, L Philip; Krawczak, Michael; Chamaillard, Mathias; Dempfle, Astrid; Andersen, Vibeke; International IBD Genetics Consortium.

I: Gastroenterology, Bind 153, Nr. 2, 08.2017, s. 550-565.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

AU - Yadav, Pankaj

AU - Ellinghaus, David

AU - Rémy, Gaëlle

AU - Freitag-Wolf, Sandra

AU - Cesaro, Anabelle

AU - Degenhardt, Frauke

AU - Boucher, Gabrielle

AU - Delacre, Myriam

AU - Peyrin-Biroulet, Laurent

AU - Pichavant, Muriel

AU - Rioux, John D

AU - Gosset, Philippe

AU - Franke, Andre

AU - Schumm, L Philip

AU - Krawczak, Michael

AU - Chamaillard, Mathias

AU - Dempfle, Astrid

AU - Andersen, Vibeke

AU - International IBD Genetics Consortium

N1 - Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2017/8

Y1 - 2017/8

N2 - BACKGROUND & AIMS: The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene-smoking interactions) that affect risk for Crohn's disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD.METHODS: We used 55 Immunochip-wide datasets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10(-/-) and Nod2(-/-) mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction.RESULTS: We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P < 5.0 × 10(-5); heterogeneity Cochrane Q test P > .05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of Interleukin 10 (il10)-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke.CONCLUSIONS: In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene-smoking interactions were confirmed in mice with disruption of Il10 and Nod2-variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.

AB - BACKGROUND & AIMS: The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene-smoking interactions) that affect risk for Crohn's disease (CD) and ulcerative colitis (UC) in a case-only study of patients and in mouse models of IBD.METHODS: We used 55 Immunochip-wide datasets that included 19,735 IBD cases (10,856 CD cases and 8879 UC cases) of known smoking status. We performed 3 meta-analyses each for CD, UC, and IBD (CD and UC combined), comparing data for never vs ever smokers, never vs current smokers, and never vs former smokers. We studied the effects of exposure to cigarette smoke in Il10(-/-) and Nod2(-/-) mice, as well as in Balb/c mice without disruption of these genes (wild-type mice). Mice were exposed to the smoke of 5 cigarettes per day, 5 days a week, for 8 weeks, in a ventilated smoking chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction.RESULTS: We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta-analysis Wald test P < 5.0 × 10(-5); heterogeneity Cochrane Q test P > .05). Twenty of these variants were located within the HLA region at 6p21. Analysis of classical HLA alleles (imputed from SNP genotypes) revealed an interaction with smoking. We replicated the interaction of a variant in NOD2 with current smoking in relation to the risk for CD (frameshift variant fs1007insC; rs5743293). We identified 2 variants in the same genomic region (rs2270368 and rs17221417) that interact with smoking in relation to CD risk. Approximately 45% of the SNPs that interact with smoking were in close vicinity (≤1 Mb) to SNPs previously associated with IBD; many were located near or within genes that regulate mucosal barrier function and immune tolerance. Smoking modified the disease risk of some variants in opposite directions for CD vs UC. Exposure of Interleukin 10 (il10)-deficient mice to cigarette smoke accelerated development of colitis and increased expression of interferon gamma in the small intestine compared to wild-type mice exposed to smoke. NOD2-deficient mice exposed to cigarette smoke developed ileitis, characterized by increased expression of interferon gamma, compared to wild-type mice exposed to smoke.CONCLUSIONS: In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene-smoking interactions were confirmed in mice with disruption of Il10 and Nod2-variants of these genes have been associated with risk for IBD. Our findings from mice and humans revealed that the effects of smoking on risk for IBD depend on genetic variants.

KW - Journal Article

U2 - 10.1053/j.gastro.2017.05.010

DO - 10.1053/j.gastro.2017.05.010

M3 - Journal article

VL - 153

SP - 550

EP - 565

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -