Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

J Rosendahl, H Kirsten, E Hegyi, P Kovacs, FU Weiss, H Laumen, P Lichtner, C Ruffert, JM Chen, E Masson, S Beer, C Zimmer, K Seltsam, H Algül, F Bühler, MJ Bruno, P Bugert, R Burkhardt, GM Cavestro, H Cichoz-LachA Farré, J Frank, G Gambaro, S Gimpfl, H Grallert, H Griesmann, R Grützmann, C Hellerbrand, P Hegyi, M Hollenbach, S Iordache, G Jurkowska, V Keim, F Kiefer, S Krug, O Landt, M Di Leo, MM Lerch, P Lévy, M Löffler, M Löhr, M Ludwig, M Macek, N Malats, E Malecka-Panas, G Malerba, K Mann, J Mayerle, S Mohr, RHM Te Morsche, M Motyka, S Mueller, T Müller, MM Nöthen, S Pedrazzoli, SP Pereira, A Peters, R Pfützer, FX Real, V Rebours, M Ridinger, M Rietschel, E Rösmann, A Saftoiu, A Schneider, HU Schulz, N Soranzo, M Soyka, P Simon, J Skipworth, F Stickel, K Strauch, M Stumvoll, PA Testoni, A Tönjes, L Werner, J Werner, N Wodarz, M Ziegler, A Masamune, J Mössner, C Férec, P Michl, JPH Drenth, H Witt, M Scholz, M Sahin-Tóth, on behalf of all members of the PanEuropean Working group on ACP

Research output: Contribution to journalArticle

Abstract

Objective: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. Design: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. Results: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. Conclusion: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Original languageEnglish
Pages (from-to)1855-1863
Number of pages9
JournalGut
Volume67
Issue number10
DOIs
Publication statusPublished - 2018

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Genome-Wide Association Study
Chronic Pancreatitis
Alcoholic Pancreatitis
Pancreatitis
Single Nucleotide Polymorphism
Trypsinogen
Population Control
Linkage Disequilibrium
Chymotrypsin
Alcoholics
Genetic Predisposition to Disease
Protein Isoforms
Hospitalization
Alcohols
Technology

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Rosendahl, J., Kirsten, H., Hegyi, E., Kovacs, P., Weiss, FU., Laumen, H., ... ACP, O. B. O. A. M. O. T. P. W. G. O. (2018). Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. Gut, 67(10), 1855-1863. https://doi.org/10.1136/gutjnl-2017-314454

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. / Rosendahl, J; Kirsten, H; Hegyi, E; Kovacs, P; Weiss, FU; Laumen, H; Lichtner, P; Ruffert, C; Chen, JM; Masson, E; Beer, S; Zimmer, C; Seltsam, K; Algül, H; Bühler, F; Bruno, MJ; Bugert, P; Burkhardt, R; Cavestro, GM; Cichoz-Lach, H; Farré, A; Frank, J; Gambaro, G; Gimpfl, S; Grallert, H; Griesmann, H; Grützmann, R; Hellerbrand, C; Hegyi, P; Hollenbach, M; Iordache, S; Jurkowska, G; Keim, V; Kiefer, F; Krug, S; Landt, O; Di Leo, M; Lerch, MM; Lévy, P; Löffler, M; Löhr, M; Ludwig, M; Macek, M; Malats, N; Malecka-Panas, E; Malerba, G; Mann, K; Mayerle, J; Mohr, S; Te Morsche, RHM; Motyka, M; Mueller, S; Müller, T; Nöthen, MM; Pedrazzoli, S; Pereira, SP; Peters, A; Pfützer, R; Real, FX; Rebours, V; Ridinger, M; Rietschel, M; Rösmann, E; Saftoiu, A; Schneider, A; Schulz, HU; Soranzo, N; Soyka, M; Simon, P; Skipworth, J; Stickel, F; Strauch, K; Stumvoll, M; Testoni, PA; Tönjes, A; Werner, L; Werner, J; Wodarz, N; Ziegler, M; Masamune, A; Mössner, J; Férec, C; Michl, P; Drenth, JPH; Witt, H; Scholz, M; Sahin-Tóth, M; ACP, on behalf of all members of the PanEuropean Working group on.

In: Gut, Vol. 67, No. 10, 2018, p. 1855-1863.

Research output: Contribution to journalArticle

Rosendahl, J, Kirsten, H, Hegyi, E, Kovacs, P, Weiss, FU, Laumen, H, Lichtner, P, Ruffert, C, Chen, JM, Masson, E, Beer, S, Zimmer, C, Seltsam, K, Algül, H, Bühler, F, Bruno, MJ, Bugert, P, Burkhardt, R, Cavestro, GM, Cichoz-Lach, H, Farré, A, Frank, J, Gambaro, G, Gimpfl, S, Grallert, H, Griesmann, H, Grützmann, R, Hellerbrand, C, Hegyi, P, Hollenbach, M, Iordache, S, Jurkowska, G, Keim, V, Kiefer, F, Krug, S, Landt, O, Di Leo, M, Lerch, MM, Lévy, P, Löffler, M, Löhr, M, Ludwig, M, Macek, M, Malats, N, Malecka-Panas, E, Malerba, G, Mann, K, Mayerle, J, Mohr, S, Te Morsche, RHM, Motyka, M, Mueller, S, Müller, T, Nöthen, MM, Pedrazzoli, S, Pereira, SP, Peters, A, Pfützer, R, Real, FX, Rebours, V, Ridinger, M, Rietschel, M, Rösmann, E, Saftoiu, A, Schneider, A, Schulz, HU, Soranzo, N, Soyka, M, Simon, P, Skipworth, J, Stickel, F, Strauch, K, Stumvoll, M, Testoni, PA, Tönjes, A, Werner, L, Werner, J, Wodarz, N, Ziegler, M, Masamune, A, Mössner, J, Férec, C, Michl, P, Drenth, JPH, Witt, H, Scholz, M, Sahin-Tóth, M & ACP, OBOAMOTPWGO 2018, 'Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis', Gut, vol. 67, no. 10, pp. 1855-1863. https://doi.org/10.1136/gutjnl-2017-314454
Rosendahl, J ; Kirsten, H ; Hegyi, E ; Kovacs, P ; Weiss, FU ; Laumen, H ; Lichtner, P ; Ruffert, C ; Chen, JM ; Masson, E ; Beer, S ; Zimmer, C ; Seltsam, K ; Algül, H ; Bühler, F ; Bruno, MJ ; Bugert, P ; Burkhardt, R ; Cavestro, GM ; Cichoz-Lach, H ; Farré, A ; Frank, J ; Gambaro, G ; Gimpfl, S ; Grallert, H ; Griesmann, H ; Grützmann, R ; Hellerbrand, C ; Hegyi, P ; Hollenbach, M ; Iordache, S ; Jurkowska, G ; Keim, V ; Kiefer, F ; Krug, S ; Landt, O ; Di Leo, M ; Lerch, MM ; Lévy, P ; Löffler, M ; Löhr, M ; Ludwig, M ; Macek, M ; Malats, N ; Malecka-Panas, E ; Malerba, G ; Mann, K ; Mayerle, J ; Mohr, S ; Te Morsche, RHM ; Motyka, M ; Mueller, S ; Müller, T ; Nöthen, MM ; Pedrazzoli, S ; Pereira, SP ; Peters, A ; Pfützer, R ; Real, FX ; Rebours, V ; Ridinger, M ; Rietschel, M ; Rösmann, E ; Saftoiu, A ; Schneider, A ; Schulz, HU ; Soranzo, N ; Soyka, M ; Simon, P ; Skipworth, J ; Stickel, F ; Strauch, K ; Stumvoll, M ; Testoni, PA ; Tönjes, A ; Werner, L ; Werner, J ; Wodarz, N ; Ziegler, M ; Masamune, A ; Mössner, J ; Férec, C ; Michl, P ; Drenth, JPH ; Witt, H ; Scholz, M ; Sahin-Tóth, M ; ACP, on behalf of all members of the PanEuropean Working group on. / Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis. In: Gut. 2018 ; Vol. 67, No. 10. pp. 1855-1863.
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title = "Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis",
abstract = "Objective: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. Design: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. Results: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95{\%} CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95{\%} CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. Conclusion: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders. {\circledC} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.",
author = "J Rosendahl and H Kirsten and E Hegyi and P Kovacs and FU Weiss and H Laumen and P Lichtner and C Ruffert and JM Chen and E Masson and S Beer and C Zimmer and K Seltsam and H Alg{\"u}l and F B{\"u}hler and MJ Bruno and P Bugert and R Burkhardt and GM Cavestro and H Cichoz-Lach and A Farr{\'e} and J Frank and G Gambaro and S Gimpfl and H Grallert and H Griesmann and R Gr{\"u}tzmann and C Hellerbrand and P Hegyi and M Hollenbach and S Iordache and G Jurkowska and V Keim and F Kiefer and S Krug and O Landt and {Di Leo}, M and MM Lerch and P L{\'e}vy and M L{\"o}ffler and M L{\"o}hr and M Ludwig and M Macek and N Malats and E Malecka-Panas and G Malerba and K Mann and J Mayerle and S Mohr and {Te Morsche}, RHM and M Motyka and S Mueller and T M{\"u}ller and MM N{\"o}then and S Pedrazzoli and SP Pereira and A Peters and R Pf{\"u}tzer and FX Real and V Rebours and M Ridinger and M Rietschel and E R{\"o}smann and A Saftoiu and A Schneider and HU Schulz and N Soranzo and M Soyka and P Simon and J Skipworth and F Stickel and K Strauch and M Stumvoll and PA Testoni and A T{\"o}njes and L Werner and J Werner and N Wodarz and M Ziegler and A Masamune and J M{\"o}ssner and C F{\'e}rec and P Michl and JPH Drenth and H Witt and M Scholz and M Sahin-T{\'o}th and ACP, {on behalf of all members of the PanEuropean Working group on}",
year = "2018",
doi = "10.1136/gutjnl-2017-314454",
language = "English",
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pages = "1855--1863",
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TY - JOUR

T1 - Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

AU - Rosendahl, J

AU - Kirsten, H

AU - Hegyi, E

AU - Kovacs, P

AU - Weiss, FU

AU - Laumen, H

AU - Lichtner, P

AU - Ruffert, C

AU - Chen, JM

AU - Masson, E

AU - Beer, S

AU - Zimmer, C

AU - Seltsam, K

AU - Algül, H

AU - Bühler, F

AU - Bruno, MJ

AU - Bugert, P

AU - Burkhardt, R

AU - Cavestro, GM

AU - Cichoz-Lach, H

AU - Farré, A

AU - Frank, J

AU - Gambaro, G

AU - Gimpfl, S

AU - Grallert, H

AU - Griesmann, H

AU - Grützmann, R

AU - Hellerbrand, C

AU - Hegyi, P

AU - Hollenbach, M

AU - Iordache, S

AU - Jurkowska, G

AU - Keim, V

AU - Kiefer, F

AU - Krug, S

AU - Landt, O

AU - Di Leo, M

AU - Lerch, MM

AU - Lévy, P

AU - Löffler, M

AU - Löhr, M

AU - Ludwig, M

AU - Macek, M

AU - Malats, N

AU - Malecka-Panas, E

AU - Malerba, G

AU - Mann, K

AU - Mayerle, J

AU - Mohr, S

AU - Te Morsche, RHM

AU - Motyka, M

AU - Mueller, S

AU - Müller, T

AU - Nöthen, MM

AU - Pedrazzoli, S

AU - Pereira, SP

AU - Peters, A

AU - Pfützer, R

AU - Real, FX

AU - Rebours, V

AU - Ridinger, M

AU - Rietschel, M

AU - Rösmann, E

AU - Saftoiu, A

AU - Schneider, A

AU - Schulz, HU

AU - Soranzo, N

AU - Soyka, M

AU - Simon, P

AU - Skipworth, J

AU - Stickel, F

AU - Strauch, K

AU - Stumvoll, M

AU - Testoni, PA

AU - Tönjes, A

AU - Werner, L

AU - Werner, J

AU - Wodarz, N

AU - Ziegler, M

AU - Masamune, A

AU - Mössner, J

AU - Férec, C

AU - Michl, P

AU - Drenth, JPH

AU - Witt, H

AU - Scholz, M

AU - Sahin-Tóth, M

AU - ACP, on behalf of all members of the PanEuropean Working group on

PY - 2018

Y1 - 2018

N2 - Objective: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. Design: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. Results: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. Conclusion: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

AB - Objective: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. Design: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. Results: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. Conclusion: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

U2 - 10.1136/gutjnl-2017-314454

DO - 10.1136/gutjnl-2017-314454

M3 - Article

VL - 67

SP - 1855

EP - 1863

JO - Gut

JF - Gut

SN - 0017-5749

IS - 10

ER -