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.
Highlights
Chronic pancreatitis (CP) is a progressive, relapsing inflammatory disorder of the pancreas which often develops in the background of genetic susceptibility [1,2,3]
To investigate whether changes in complex formation between human procarboxypeptidases and proelastases alter risk for CP, we investigated the frequency of variants c.722G>C (p.G241A) in CELA3A and c.722C>G (p.A241G) in CELA3B in subjects with CP and controls without pancreatic disease
We sequenced exon 7 and flanking intronic regions of CELA3A and CELA3B in 225 patients and 300 controls from the registry of the Hungarian Pancreatic Study Group. This CP cohort consisted of 120 alcoholic chronic pancreatitis (ACP) and 105 idiopathic chronic pancreatitis (ICP) patients
Summary
Chronic pancreatitis (CP) is a progressive, relapsing inflammatory disorder of the pancreas which often develops in the background of genetic susceptibility [1,2,3]. It is possible that reduced CPA1 secretion might cause predisposition to CP by other mechanisms In this respect, we noted that procarboxypeptidase A (proCPA) often forms complexes with proelastases in the mammalian pancreas ([11] and references therein). The polymorphic nature of amino-acid 241 offers the unique opportunity to perform a genetic association study to investigate whether changes in complex formation between proelastases and procarboxypeptidases affect CP risk. To this end, in the present paper we compared allele frequencies of variants p.G241A in CELA3A and p.A241G in CELA3B between subjects with CP and controls without pancreatic disease
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