Risk of chronic pancreatitis in carriers of loss-of-function CTRC variants: A meta-analysis

Amanda Takáts; Gergő Berke; Noémi Gede; Balázs Csaba Németh; Heiko Witt; Stanisław Głuszek; Agnieszka Magdalena Rygiel; Péter Hegyi; Miklós Sahin-Tóth; Eszter Hegyi

doi:10.1371/journal.pone.0268859

Risk of chronic pancreatitis in carriers of loss-of-function CTRC variants: A meta-analysis

PLoS One. 2022 May 20;17(5):e0268859. doi: 10.1371/journal.pone.0268859. eCollection 2022.

Authors

Affiliations

¹ Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
² Department of Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary.
³ Pediatric Nutritional Medicine & Else Kröner-Fresenius-Centre for Nutritional Medicine (EKFZ), Technical University Munich (TUM), Munich, Germany.
⁴ Collegium Medicum Jan Kochanowski University, Kielce, Poland.
⁵ Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.
⁶ Centre for Translational Medicine, Semmelweis University, Budapest, Hungary.
⁷ Department of Surgery, University of California Los Angeles, Los Angeles, California, United States of America.

Abstract

The digestive protease chymotrypsin C (CTRC) protects the pancreas against pancreatitis by degrading potentially harmful trypsinogen. Loss-of-function genetic variants in CTRC increase risk for chronic pancreatitis (CP) with variable effect size, as judged by the reported odds ratio (OR) values. Here, we performed a meta-analysis of published studies on four variants that alter the CTRC amino-acid sequence, are clinically relatively common (global carrier frequency in CP >1%), reproducibly showed association with CP and their loss of function phenotype was verified experimentally. We found strong enrichment of CTRC variants p.A73T, p.V235I, p.K247_R254del, and p.R245W in CP cases versus controls, yielding OR values of 6.5 (95% confidence interval (CI) 2.4-17.8), 4.5 (CI 2.2-9.1), 5.4 (CI 2.6-11.0), and 2.6 (CI 1.6-4.2), respectively. Subgroup analysis demonstrated disease association of variants p.K247_R254del and p.R245W in alcoholic CP with similar effect sizes as seen in the overall CP group. Homozygosity or compound heterozygosity were rare and seemed to be associated with higher risk. We also identified a so far unreported linkage disequilibrium between variant p.K247_R254del and the common c.180C>T (p.G60 =) haplotype. Taken together, the results indicate that heterozygous loss-of-function CTRC variants increase the risk for CP approximately 3-7-fold. This meta-analysis confirms the clinical significance of CTRC variants and provides further justification for the genetic screening of CP patients.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Chymotrypsin* / genetics
Genetic Predisposition to Disease
Humans
Mutation
Pancreatitis, Alcoholic* / genetics
Pancreatitis, Chronic* / genetics

Substances

Chymotrypsin
chymotrypsin C

Grants and funding

This work was supported by the Eötvös Loránd Research Network award 460051 to EH, a grant from the Research Fund of the University of Pécs to EH, the National Institutes of Health (NIH) grant R01 DK082412 to MST, the National Research Development and Innovation Fund grant ÚNKP-21-3-I-PTE-1081 to GB, the National Research Development and Innovation Office grant K131996 to PH, and FK124632 to BCN, the Economic Development and Innovation Operative Programme Grant GINOP 2.3.2-15-2016-00048 to PH, the Human Resources Development Operational Programme Grant EFOP-3.6.2-16-2017-00006 to PH, the National Science Centre, Poland, grant 2015/19/B/NZ5/02224 to AMR and the Else Kröner-Fresenius-Stiftung (EKFS) 2017_A108 – EKFZ-Witt to HW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.