No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort. Issue 8 (30th May 2017)

• Record Type: Journal Article
• Authors: Wu, Hao; Zhou, Dai‐Zhan; Berki, Dorottya; Geisz, Andrea; Zou, Wen‐Bin; Sun, Xiao‐Tian; Hu, Liang‐Hao; Zhao, Zhen‐Hua; Zhao, An‐Jing; He, Lin; Cooper, David N.; Férec, Claude; Chen, Jian‐Min; Li, Zhao‐Shen; Sahin‐Tóth, Miklós; Liao, Zhuan
• Is Part Of: Human mutation. Volume 38:Issue 8(2017)
• Page Start: 959
• Page End: 963
• Publication Date: 2017-05-30
• Subjects: CPA1 gene -- idiopathic chronic pancreatitis -- missense mutations -- next‐generation sequencing -- rare variants; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23254
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : Rare functionally defective CPA1 variants (defined as exhibiting enzymatic activity <20% of the wild‐type in the conditioned medium of transfected cells) were recently reported to predispose to nonalcoholic chronic pancreatitis, mainly the idiopathic subtype. However, we failed to confirm this finding in the context of a large Chinese idiopathic chronic pancreatitis cohort (1112 patients and 1580 controls). One reason may be that enzymatic activity is not the best proxy marker for the functional effect of the chronic pancreatitis‐associated CPA1 variants. Abstract: Rare functionally defective carboxypeptidase A1 ( CPA1 ) variants have been reported to predispose to nonalcoholic chronic pancreatitis, mainly the idiopathic subtype. However, independent replication has so far been lacking, particularly in Asian cohorts where initial studies employed small sample sizes. Herein we performed targeted next‐generation sequencing of the CPA1 gene in 1, 112 Han Chinese idiopathic chronic pancreatitis (ICP) patients—the largest ICP cohort so far analyzed in a single population—and 1, 580 controls. Sanger sequencing was used to validate called variants, and the CPA1 activity and secretion of all newly found variants were measured. A total of 18 rare CPA1 variants were characterized, 11 of which have not been previously described. However, no significant association was noted with ICP irrespective of whether all rare variants [20 out of 1, 112 (1.8%) in patients vs. 24 out of 1, 580 (1.52%) in controls; P = 0.57] or functionally impaired variants [three out of 1, 112 (0.27%) in patients vs. two out of 1, 580 (0.13%) in controls; P = 0.68] were considered.