title: Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis.
abstract: Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both inCELA3A(p.G241A) andCELA3B(p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 ofCELA3AandCELA3Bin a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% forCELA3Ap.G241A and 1.5% forCELA3Bp.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T inCELA3Bshowed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39-0.89,p= 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 inCELA3AandCELA3Bare not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.
authors.affiliation: Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA. andrea.parniczky@gmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Párniczky
authors.affiliation: Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA. heszter@bu.edu.
authors.forename: Eszter
authors.initials: E
authors.lastname: Hegyi
authors.affiliation: Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA. tothannadr@gmail.com.
authors.forename: Anna Zsófia
authors.initials: AZ
authors.lastname: Tóth
authors.affiliation: First Department of Surgery, Semmelweis University, 1082 Budapest, Hungary. szucs.akos@gmail.com.
authors.forename: Ákos
authors.initials: Á
authors.lastname: Szücs
authors.affiliation: Institute for Translational Medicine, University of Pécs, 7624 Pécs, Hungary. szentesiai@gmail.com.|First Department of Medicine, University of Szeged, 6720 Szeged, Hungary. szentesiai@gmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Szentesi
authors.affiliation: First Department of Medicine, University of Pécs, 7624 Pécs, Hungary. vincze.aron@pte.hu.
authors.forename: Áron
authors.initials: Á
authors.lastname: Vincze
authors.affiliation: Department of Gastroenterology, St. George Teaching Hospital of County Fejér, 8000 Székesfehérvár, Hungary. fizbeki@gmail.com.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Izbéki
authors.affiliation: First Department of Medicine, University of Szeged, 6720 Szeged, Hungary. nemeth.balazs@med.u-szeged.hu.
authors.forename: Balázs Csaba
authors.initials: BC
authors.lastname: Németh
authors.affiliation: Institute for Translational Medicine, University of Pécs, 7624 Pécs, Hungary. hegyi2009@gmail.com.|First Department of Medicine, University of Szeged, 6720 Szeged, Hungary. hegyi2009@gmail.com.
authors.forename: Péter
authors.initials: P
authors.lastname: Hegyi
authors.affiliation: Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA. miklos@bu.edu.
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
mesh_terms: D001483:Base Sequence; D002268:Carboxypeptidases / Q000378:metabolism*; D002460:Cell Line; D004792:Enzyme Precursors / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D010179:Pancreas / Q000473:pathology; D010196:Pancreatic Elastase / Q000235:genetics* / Q000378:metabolism*; D050500:Pancreatitis, Chronic / Q000235:genetics* / Q000473:pathology*; D011485:Protein Binding; D017422:Sequence Analysis, DNA
chemical_list: D004792:Enzyme Precursors; D002268:Carboxypeptidases; C022443:proelastase; C000617121:CELA3A protein, human; C000617122:CELA3B protein, human; D010196:Pancreatic Elastase
keywords: chronic pancreatitis; digestive protease; elastase; pancreas; zymogen complexes