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

Andrea Párniczky, Eszter Hegyi, Anna Zsófia Tóth, Ákos Szücs, Andrea Szentesi, A. Vincze, Ferenc Izbéki, Balázs Csaba Németh, Péter Hegyi, Miklós Sahin-Tóth

Research output: Contribution to journalArticle

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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 in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in 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% for CELA3A p.G241A and 1.5% for CELA3B p.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 in CELA3B showed 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 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.

Original languageEnglish
Article number2148
JournalInternational Journal of Molecular Sciences
Volume17
Issue number12
DOIs
Publication statusPublished - Dec 20 2016

Fingerprint

Carboxypeptidases A
Pancreatic Elastase
Chronic Pancreatitis
Medical Genetics
Chymotrypsin
genes
Exons
Genes
functional analysis
Gene Conversion
Functional analysis
secretions
amino acids
Amino acids
Substitution reactions
Alcoholic Pancreatitis
Association reactions
substitutes
Amino Acids
Defects

Keywords

  • Chronic pancreatitis
  • Digestive protease
  • Elastase
  • Pancreas
  • Zymogen complexes

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Computer Science Applications
  • Spectroscopy
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

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. / Párniczky, Andrea; Hegyi, Eszter; Tóth, Anna Zsófia; Szücs, Ákos; Szentesi, Andrea; Vincze, A.; Izbéki, Ferenc; Németh, Balázs Csaba; Hegyi, Péter; Sahin-Tóth, Miklós.

In: International Journal of Molecular Sciences, Vol. 17, No. 12, 2148, 20.12.2016.

Research output: Contribution to journalArticle

Párniczky, Andrea ; Hegyi, Eszter ; Tóth, Anna Zsófia ; Szücs, Ákos ; Szentesi, Andrea ; Vincze, A. ; Izbéki, Ferenc ; Németh, Balázs Csaba ; Hegyi, Péter ; Sahin-Tóth, Miklós. / 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. In: International Journal of Molecular Sciences. 2016 ; Vol. 17, No. 12.
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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 in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in 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{\%} for CELA3A p.G241A and 1.5{\%} for CELA3B p.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 in CELA3B showed 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 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.",
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AU - Hegyi, Eszter

AU - Tóth, Anna Zsófia

AU - Szücs, Ákos

AU - Szentesi, Andrea

AU - Vincze, A.

AU - Izbéki, Ferenc

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AB - 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 in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in 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% for CELA3A p.G241A and 1.5% for CELA3B p.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 in CELA3B showed 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 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.

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