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. 2018 Nov 12;9(11):204.
doi: 10.1038/s41424-018-0069-5.

SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis

Wen-Bin Zou  1   2 , Xin-Ying Tang  1   2 , Dai-Zhan Zhou  3 , Yang-Yang Qian  1   2 , Liang-Hao Hu  1 , Fei-Fei Yu  4 , Dong Yu  5 , Hao Wu  1   2 , Shun-Jiang Deng  2 , Jin-Huan Lin  1 , An-Jing Zhao  1 , Zhen-Hua Zhao  1 , Hong-Yu Wu  2 , Jia-Hui Zhu  1 , Wei Qian  1 , Lei Wang  1 , Lei Xin  1 , Min-Jun Wang  6 , Li-Juan Wang  2 , Xue Fang  2 , Lin He  7 , Emmanuelle Masson  8 , David N Cooper  9 , Claude Férec  8 , Zhao-Shen Li  10   11 , Jian-Min Chen  12 , Zhuan Liao  13   14
Affiliations

SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis

Wen-Bin Zou et al. Clin Transl Gastroenterol. .

Abstract

Objectives: Rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes have been strongly associated with a risk of developing chronic pancreatitis (CP). However, their potential impact on the age of disease onset and clinical outcomes, as well as their potential interactions with environmental risk factors, remain unclear. These issues are addressed here in a large Chinese CP cohort.

Methods: We performed targeted next-generation sequencing of the four CP-associated genes in 1061 Han Chinese CP patients and 1196 controls. To evaluate gene-environment interactions, the patients were divided into three subgroups, idiopathic CP (ICP; n = 715), alcoholic CP (ACP; n = 206), and smoking-associated CP (SCP; n = 140). The potential impact of rare pathogenic variants on the age of onset of CP and clinical outcomes was evaluated using the Kaplan-Meier model.

Results: We identified rare pathogenic genotypes involving the SPINK1, PRSS1, CTRC, and/or CFTR genes in 535 (50.42%) CP patients but in only 71 (5.94%) controls (odds ratio = 16.12; P < 0.001). Mutation-positive patients had significantly earlier median ages at disease onset and at diagnosis of pancreatic stones, diabetes mellitus and steatorrhea than mutation-negative ICP patients. Pathogenic genotypes were present in 57.1, 39.8, and 32.1% of the ICP, ACP, and SCP patients, respectively, and influenced age at disease onset and clinical outcomes in all subgroups.

Conclusions: We provide evidence that rare pathogenic variants in the SPINK1, PRSS1, CTRC, and CFTR genes significantly influence the age of onset and clinical outcomes of CP. Extensive gene-environment interactions were also identified.

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Conflict of interest statement

Guarantor of the article: Zhuan Liao, MD.

Specific author contributions: W.-B.Z., X.-Y.T. and D.-Z.Z. performed the genetic and statistical analysis, with substantial contributions from L.-H.H., D.Y., L.H., F.-F.Y., W.Q., L.-J.W., M.-J.W., X.F. and H.W. Z.-H.Z. and H.-Y.W. collected the blood samples and performed DNA extraction. J.-H.L, X.-Y.T. and S.-J.D. performed the Sanger sequencing. Y.-Y.Q., A.-J.Z., J.-H.Z., L.X. and L.W. recorded the clinical data. W.-B.Z., X.-Y.T., E.M., C.F., Z.L. and J.-M.C. contributed to variant classification. J.-M.C., W.-B.Z. and Z.L. wrote the manuscript. D.N.C. critically revised with manuscript. Z.-S.L., W.-B.Z. and Z.L. obtained the funding. All authors contributed to data interpretation and revision of the manuscript and approved the final manuscript.

Financial support: Support for this study came from the National Natural Science Foundation of China (Grant Nos. 81470884, 81770636, 81422010 [Z.L.], 81700565 [W.B.Z.]), the China Chang Jiang Scholars Program of Ministry of Education (Grant No. Q2015190 [Z.L.]), the Shuguang Program of Shanghai (Grant No. 15SG33 [Z.L.]), the Shanghai Pujiang Program (Grant No. 17PJD044 [W.B.Z.]), the Precision Medicine Program of the Second Military Medical University (Grant No. 2017JZ02 [Z.S.L.]), and the Scientific Innovation Program of Shanghai Municipal Education Committee [Z.L.]. The funding bodies had no role in the study design, the collection, analysis, and interpretation of data, or the writing of the article and the decision to submit it for publication.

Potential competing interests: None.

Figures

Fig. 1
Fig. 1. Pathogenic genotypes affect disease onset and clinical outcomes of CP.
Kaplan–Meier plots of age at disease onset (a), age at diagnosis of pancreatic stones (b), age at diagnosis of diabetes mellitus (c), and age at diagnosis of steatorrhea (d) for all Han Chinese CP patients with and without pathogenic SPINK1, PRSS1, CTRC, and/or CFTR genotypes. Red, patients with pathogenic genotypes. Blue, patients without pathogenic genotypes
Fig. 2
Fig. 2. Comparison of overall prevalence and relative distribution of pathogenic genotypes in Han Chinese ICP, ACP and SCP patients.
Data from all patients are also included for the purposes of comparison. The genotypes are defined as in Table 2 and Supplementary Table 3
Fig. 3
Fig. 3. Impact of different pathogenic genotypes on disease onset and cumulative rate of pancreatic stones in ICP.
Kaplan–Meier plots of age at disease onset (a) and of age at diagnosis of pancreatic stones (b) for the four most frequent pathogenic genotypes in the Han Chinese ICP patients. PRSS1 c.365G>A (p.Arg122His) was included for the purposes of comparison
See this image and copyright information in PMC

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