Rare Functional CPA1 Variants and Chronic Pancre...
Procarboxypeptidase A1 is the precursor and inactive form of the digestive enzyme carboxypeptidase A1（CPA1；OMIM #114850）.Procarboxypeptidase A1，a component of the pancreatic zymogen activation cascade（Chen and Férec 2009），is the sec most abundantly synthesized protein after trypsinogens in the pancreatic juice（Scheele et al.1981）.Earlier findings from the study of the PRSS1，PRSS2，SPINK1 and CTRC genes prompted Witt and colleagues to analyse the CPA1 as a candidate gene for chronic pancreatitis（Witt et al.2013）.They found an overrepresentation of functionally defective CPA1 variants（defined as having enzyme activity＜20%of the wild-type）in German patients with nonalcoholic chronic pancreatitis（NACP；including idiopathic and familial subtypes）as compared with controls（3.1%（29/944）vs.0.1%（5/3938）；odds ratio（OR）=24.9，P=1.5 × 10-16）.The association was strongest for the German patients aged≤10 years，where the detection frequency was nearly 10%（22/228）and the corresponding OR was as high as 84.0（Witt et al.2013）.Functionally impaired CPA1variantswere also found to be significantly overrepresented in NACP patients in a European replication study，albeit with an approximately seven-fold lower OR and a much higher P value（Witt et al.2013）.Replications in two small Asian cohorts provided further supporting data（Witt et al.2013）.However，given the remarkable differences in the occurrence and distribution of rare functional CPA1 variants between the different populations and the small sizes of the two Asian cohorts so far analysed，further independent replication in larger studies is required（MacArthur et al.2014）.(https://www.daowen.com)
The two other human pancreatic carboxypeptidase genes，CPA2 and CPB1，were recently analysed in 477 Japanese patients with chronic pancreatitis（234 alcoholic，243 nonalcoholic）and in 497 German patients with nonalcoholic chronic pancreatitis by targeted next-generation sequencing and/or Sanger sequencing.Secretion and the enzymatic activity of CPA2 and CPB1 variants were both determined after transfection into HEK 293T cells.None of the CPA2 or CPB1 variants，including those resulting in a marked loss of function，were found to be overrepresented in patients with chronic pancreatitis（Nakano et al.2015）.