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.
- Genome wide association study
- chronic pancreatitis
- genetic rearrangement
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JPHD, HW, MS and MS-T contributed equally to the supervision of the work.
JR and HK contributed equally.
Contributors JR, PK, JPHD, HW, MS, MS-T and HK conceived, designed and directed the study. JR, EH, FUW, PL, CR and CZ performed genotyping. JR, HK and MS-T drafted and revised the manuscript with substantial help from FXR, JPHD, HW, PK, EH and MS. MS and HK performed bioinformatics work. JR , EH , FUW, HL, PL, CR, JMC, EM, HW, MS, MS-T and HK designed, performed and interpreted genetic analyses. EH and MS-T carried out functional analysis. All other co-authors recruited study subjects, collected clinical data and/or provided genomic DNA samples. All authors approved the final manuscript and contributed critical revisions to its intellectual content.
Funding This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants RO 3929/1–1, RO 3929/2-1 and RO3929/5-1 (to JR), Wi 2036/2-2 and Wi 2036/2-3 (to HW) and SFB 1052 (to MB, MS, AT, PK), SFB 1052 C01, B01, B03; SPP 1629 TO 718/2-1 (to AT) by a grant of the Colora Stiftung gGmbH (to JR), the Else Kröner-Fresenius-Foundation (EKFS) (to HW), NIH grants R01DK058088, R01DK082412; and R01DK095753 (to MS-T), a grant from the National Pancreas Foundation (to EH), the Institut National de la Santé et de la Recherche Médicale (INSERM; to CF), the Programme Hospitalier de Recherche Clinique (PHRC R 08-04; to CF), the French Association des Pancréatites Chroniques Héréditaires (to CF), the Council of Scientific and Industrial Research (CSIR) (to CF), by grants of the European Regional Development Fund (ERDF) V-630-F-150-2012/133 and V630-S-150-2012/132 (to FUW), by grants 310030_138747 and 310030_169196 from the Swiss National Funds (to FS) and by grants RTICC from Instituto de Salud Carlos III (RD12/0036/0034) and SAF 2015–70857 from Ministerio de Economía y Competitividad (Madrid, Spain) (co-funded by the ERDF-EU) (to FXR) and Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (Grant #PI1501573) (to NM). SPP was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by funds of the Free State of Saxony within the framework of the excellence initiative (project numbers 713-241202, 14505/2470, 14575/2470). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was financed by a grant from the BMBF to the German Center for Diabetes Research (DZD) and a grant from the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Düsseldorf, Germany). It was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethic Committee of the University of Leipzig.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All chip data are available upon request.
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