TY - JOUR
T1 - Loss-of-function variant in chymotrypsin like elastase 3B (CELA3B) is associated with non-alcoholic chronic pancreatitis
AU - Tóth, Andrea
AU - Demcsák, Alexandra
AU - Zankl, Florence
AU - Oracz, Grzegorz
AU - Unger, Lara Sophie
AU - Bugert, Peter
AU - Laumen, Helmut
AU - Párniczky, Andrea
AU - Hegyi, Péter
AU - Rosendahl, Jonas
AU - Gambin, Tomasz
AU - Płoski, Rafał
AU - Koziel, Dorota
AU - Gluszek, Stanisław
AU - Lindgren, Fredrik
AU - Löhr, J. Matthias
AU - Sahin-Tóth, Miklós
AU - Witt, Heiko
AU - Rygiel, Agnieszka Magdalena
AU - Ewers, Maren
AU - Hegyi, Eszter
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/9
Y1 - 2022/9
N2 - 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: 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: 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: 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.
AB - 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: 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: 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: 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.
KW - CELA3B
KW - Chronic pancreatitis
KW - Elastases
KW - Genetics
UR - http://www.scopus.com/inward/record.url?scp=85132952021&partnerID=8YFLogxK
U2 - 10.1016/j.pan.2022.06.258
DO - 10.1016/j.pan.2022.06.258
M3 - Article
C2 - 35773178
AN - SCOPUS:85132952021
SN - 1424-3903
VL - 22
SP - 713
EP - 718
JO - Pancreatology
JF - Pancreatology
IS - 6
ER -