TY - JOUR
T1 - Risk of chronic pancreatitis in carriers of loss-of-function CTRC variants
T2 - A meta-analysis
AU - Takáts, Amanda
AU - Berke, Gergő
AU - Gede, Noémi
AU - Németh, Balázs Csaba
AU - Witt, Heiko
AU - Głuszek, Stanisław
AU - Rygiel, Agnieszka Magdalena
AU - Hegyi, Péter
AU - Sahin-Tóth, Miklós
AU - Hegyi, Eszter
N1 - Publisher Copyright:
© 2022 Takáts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2022/5
Y1 - 2022/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85130446309&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0268859
DO - 10.1371/journal.pone.0268859
M3 - Article
C2 - 35594281
AN - SCOPUS:85130446309
SN - 1932-6203
VL - 17
JO - PLoS ONE
JF - PLoS ONE
IS - 5 May
M1 - e0268859
ER -