Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease

Marijn C Visschedijk; Lieke M Spekhorst; Shih-Chin Cheng; Ellen S van Loo; B H Dianne Jansen; Tjasso Blokzijl; Hyunsuk Kil; Dirk J de Jong; Marieke Pierik; Jeroen P W J Maljaars; C Janneke van der Woude; Adriaan A van Bodegraven; Bas Oldenburg; Mark Löwenberg; Vincent B Nieuwenhuijs; Floris Imhann; Suzanne van Sommeren; Rudi Alberts; Ramnik J Xavier; Gerard Dijkstra; Klaas Nico Faber; C Marcelo Aldaz; Rinse K Weersma; Eleonora A M Festen

doi:10.1093/ecco-jcc/jjy001

Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease

Marijn C Visschedijk, Lieke M Spekhorst, Shih-Chin Cheng, Ellen S van Loo, B H Dianne Jansen, Tjasso Blokzijl, Hyunsuk Kil, Dirk J de Jong, Marieke Pierik, Jeroen P W J Maljaars, C Janneke van der Woude, Adriaan A van Bodegraven, Bas Oldenburg, Mark Löwenberg, Vincent B Nieuwenhuijs, Floris Imhann, Suzanne van Sommeren, Rudi Alberts, Ramnik J Xavier, Gerard DijkstraKlaas Nico Faber, C Marcelo Aldaz, Rinse K Weersma, Eleonora A M Festen

Onderzoeksoutput: Article › Academic › peer review

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Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD.

Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD.

Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910(-11)], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079].

Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.

Originele taal-2	English
Pagina's (van-tot)	582-588
Aantal pagina's	7
Tijdschrift	Journal of Crohn's and Colitis
Volume	12
Nummer van het tijdschrift	5
Vroegere onlinedatum	19-jan.-2018
DOI's	https://doi.org/10.1093/ecco-jcc/jjy001
Status	Published - mei-2018

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10.1093/ecco-jcc/jjy001

Genomic and expression analyses identify a disease modifying variant for fibrostenotic Crohn’s diseaseFinal publisher's version, 1,12 MBLicentie: Taverne

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Parel Infammatory Bowel Disease (IBD)
Dijkstra, G. (Creator), F.M., T. (Other), Lowenberg, M. (Creator), Bosma, C. (Data Manager) & Terpstra, F. (Data Manager), University of Groningen, 2017
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Visschedijk, M. C., Spekhorst, L. M., Cheng, S.-C., van Loo, E. S., Jansen, B. H. D., Blokzijl, T., Kil, H., de Jong, D. J., Pierik, M., Maljaars, J. P. W. J., van der Woude, C. J., van Bodegraven, A. A., Oldenburg, B., Löwenberg, M., Nieuwenhuijs, V. B., Imhann, F., van Sommeren, S., Alberts, R., Xavier, R. J., ... Festen, E. A. M. (2018). Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease. Journal of Crohn's and Colitis, 12(5), 582-588. https://doi.org/10.1093/ecco-jcc/jjy001

@article{1b288cddac724d2d866f0ccbb28f0437,

title = "Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease",

abstract = "Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD.Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD.Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910(-11)], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079].Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.",

keywords = "Crohn's disease, fibrosis, genetics, INFLAMMATORY-BOWEL-DISEASE, WIDE ASSOCIATION, INTESTINAL FIBROSIS, RISK, LOCI, SUSCEPTIBILITY, IDENTIFICATION, VISUALIZATION, PHENOTYPES",

author = "Visschedijk, {Marijn C} and Spekhorst, {Lieke M} and Shih-Chin Cheng and {van Loo}, {Ellen S} and Jansen, {B H Dianne} and Tjasso Blokzijl and Hyunsuk Kil and {de Jong}, {Dirk J} and Marieke Pierik and Maljaars, {Jeroen P W J} and {van der Woude}, {C Janneke} and {van Bodegraven}, {Adriaan A} and Bas Oldenburg and Mark L{\"o}wenberg and Nieuwenhuijs, {Vincent B} and Floris Imhann and {van Sommeren}, Suzanne and Rudi Alberts and Xavier, {Ramnik J} and Gerard Dijkstra and Faber, {Klaas Nico} and Aldaz, {C Marcelo} and Weersma, {Rinse K} and Festen, {Eleonora A M}",

year = "2018",

month = may,

doi = "10.1093/ecco-jcc/jjy001",

language = "English",

volume = "12",

pages = "582--588",

journal = "Journal of Crohn's and Colitis",

issn = "1873-9946",

publisher = "Oxford University Press",

number = "5",

}

Visschedijk, MC , Spekhorst, LM, Cheng, S-C, van Loo, ES, Jansen, BHD , Blokzijl, T, Kil, H, de Jong, DJ, Pierik, M, Maljaars, JPWJ, van der Woude, CJ, van Bodegraven, AA, Oldenburg, B, Löwenberg, M, Nieuwenhuijs, VB, Imhann, F, van Sommeren, S, Alberts, R, Xavier, RJ, Dijkstra, G , Faber, KN, Aldaz, CM, Weersma, RK & Festen, EAM 2018, 'Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease', Journal of Crohn's and Colitis, vol. 12, nr. 5, blz. 582-588. https://doi.org/10.1093/ecco-jcc/jjy001

TY - JOUR

T1 - Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease

AU - Visschedijk, Marijn C

AU - Spekhorst, Lieke M

AU - Cheng, Shih-Chin

AU - van Loo, Ellen S

AU - Jansen, B H Dianne

AU - Blokzijl, Tjasso

AU - Kil, Hyunsuk

AU - de Jong, Dirk J

AU - Pierik, Marieke

AU - Maljaars, Jeroen P W J

AU - van der Woude, C Janneke

AU - van Bodegraven, Adriaan A

AU - Oldenburg, Bas

AU - Löwenberg, Mark

AU - Nieuwenhuijs, Vincent B

AU - Imhann, Floris

AU - van Sommeren, Suzanne

AU - Alberts, Rudi

AU - Xavier, Ramnik J

AU - Dijkstra, Gerard

AU - Faber, Klaas Nico

AU - Aldaz, C Marcelo

AU - Weersma, Rinse K

AU - Festen, Eleonora A M

PY - 2018/5

Y1 - 2018/5

N2 - Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD.Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD.Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910(-11)], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079].Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.

AB - Background and Aims: Crohn's disease [CD] is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD.Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [SNPs] with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis [recurrent after surgery] and 619 cases with purely inflammatory CD.Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910(-11)], located on chromosome 16, in lncRNA RP11-679B19.1, an lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-beta and downstream genes in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-beta compared to patients homozygous for the wild-type [G] allele [p = 0.0079].Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.

KW - Crohn's disease

KW - fibrosis

KW - genetics

KW - INFLAMMATORY-BOWEL-DISEASE

KW - WIDE ASSOCIATION

KW - INTESTINAL FIBROSIS

KW - RISK

KW - LOCI

KW - SUSCEPTIBILITY

KW - IDENTIFICATION

KW - VISUALIZATION

KW - PHENOTYPES

U2 - 10.1093/ecco-jcc/jjy001

DO - 10.1093/ecco-jcc/jjy001

M3 - Article

C2 - 29361163

SN - 1873-9946

VL - 12

SP - 582

EP - 588

JO - Journal of Crohn's and Colitis

JF - Journal of Crohn's and Colitis

IS - 5

ER -

Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease

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