Exploring the enigmatic association between PNLIP variants and risk of chronic pancreatitis in a large Chinese cohort

Brett M. Cassidy, Fei Jiang, Jianguo Lin, Jian Min Chen, Grace E. Curry, Guo Xiu Ma, Steven J. Wilhelm, Shun Jiang Deng, Guoying Zhu, Zhuan Liao, Mark E. Lowe, Xunjun Xiao, Wen Bin Zou

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background & Aims: Protease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP. Methods: All coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control. Results: We identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress. Conclusions: Our genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP.

Original languageEnglish
Pages (from-to)511-521
Number of pages11
JournalPancreatology
Volume24
Issue number4
DOIs
StatePublished - Jun 2024

Keywords

  • Case-control study
  • Genetics
  • Pancreatic triglyceride lipase
  • Predisposition to disease

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