Loss-of-function variant in chymotrypsin like elastase 3B (CELA3B) is associated with non-alcoholic chronic pancreatitis.
CELA3B
Chronic pancreatitis
Elastases
Genetics
Journal
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
ISSN: 1424-3911
Titre abrégé: Pancreatology
Pays: Switzerland
ID NLM: 100966936
Informations de publication
Date de publication:
Sep 2022
Sep 2022
Historique:
received:
20
02
2022
revised:
20
05
2022
accepted:
19
06
2022
pubmed:
1
7
2022
medline:
15
9
2022
entrez:
30
6
2022
Statut:
ppublish
Résumé
Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP. We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants. In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L. Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.
Sections du résumé
BACKGROUND
BACKGROUND
Genetic alterations in digestive enzymes have been associated with chronic pancreatitis (CP). Recently, chymotrypsin like elastase 3B (CELA3B) emerged as a novel risk gene. Thus, we evaluated CELA3B in two European cohorts with CP.
METHODS
METHODS
We analyzed all 8 CELA3B exons in 550 German non-alcoholic CP (NACP) patients and in 241 German controls by targeted DNA sequencing. In addition, we analyzed exons 6 and 7 by Sanger sequencing and the c.129+1G>A variant by melting curve analysis in 1078 further German controls. As replication cohort, we investigated up to 243 non-German European NACP patients and up to 1665 controls originating from Poland, Hungary, and Sweden. We assessed the cellular secretion and the elastase activity of recombinant CELA3B variants.
RESULTS
RESULTS
In the German discovery cohort, we detected a splice-site variant in intron 2, c.129+1G>A, in 9/550 (1.64%) CP patients and in 5/1319 (0.38%) controls (P=0.007, OR=4.4, 95% CI=1.5-13.0). In the European replication cohort, this variant was also enriched in patients (9/178 [5.06%]) versus controls (13/1247 [1.04%]) (P=0.001, OR=5.1, 95% CI=2.1-12.0). We did not find the two previously reported codon 90 variants, p.R90C and p.R90L.
CONCLUSIONS
CONCLUSIONS
Our data indicate that CELA3B is a susceptibility gene for CP. In contrast to previous reports suggesting that increased CELA3B activity is associated with CP risk, the splice-site variant identified here is predicted to cause diminished CELA3B expression. How reduced CELA3B function predisposes to pancreatitis remains to be elucidated.
Identifiants
pubmed: 35773178
pii: S1424-3903(22)00453-7
doi: 10.1016/j.pan.2022.06.258
pmc: PMC9474678
mid: NIHMS1831800
pii:
doi:
Substances chimiques
Chymotrypsin
EC 3.4.21.1
CELA3B protein, human
EC 3.4.21.36
Pancreatic Elastase
EC 3.4.21.36
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
713-718Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK058088
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK082412
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117809
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors report no conflicts of interest.
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