SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis.
SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis.
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SPINK1、PRSS1、CTRC 和 CFTR 基因型影响慢性胰腺炎的发病和临床结果
DOI：
10.1038/s41424-018-0069-5
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发表时间：
2018-11-12
影响因子：
3.6
通讯作者：
Liao Z
中科院分区：
文献类型：
--
作者：
Zou WB;Tang XY;Zhou DZ;Qian YY;Hu LH;Yu FF;Yu D;Wu H;Deng SJ;Lin JH;Zhao AJ;Zhao ZH;Wu HY;Zhu JH;Qian W;Wang L;Xin L;Wang MJ;Wang LJ;Fang X;He L;Masson E;Cooper DN;Férec C;Li ZS;Chen JM;Liao Z
目的：SPINK 1、PRSS 1、CTRC和CFTR基因中的罕见致病性变异与慢性胰腺炎（CP）的发生风险密切相关。然而，它们对发病年龄和临床结果的潜在影响，以及它们与环境风险因素的潜在相互作用，仍不清楚。这些问题在一个大型的中国CP队列中得到解决。方法：我们对1061名中国汉族CP患者和1196名对照者的4个CP相关基因进行了靶向下一代测序。为了评估基因-环境相互作用，将患者分为三个亚组，特发性CP（ICP; n = 715），酒精性CP（ACP; n = 206）和吸烟相关CP（SCP; n = 140）。使用Kaplan-Meier模型评价了罕见致病性变异对CP发病年龄和临床结局的潜在影响。结果如下：我们在535例（50.42%）CP患者中发现了涉及SPINK 1、PRSS 1、CTRC和/或CFTR基因的罕见致病基因型，而在对照组中仅发现了71例（5.94%）（比值比= 16.12; P< 0.001）。突变阳性患者在疾病发作和诊断胰腺结石、糖尿病和脂肪肝时的中位年龄显著早于突变阴性ICP患者。ICP、ACP和SCP患者的致病基因型分别为57.1%、39.8%和32.1%，并影响所有亚组的发病年龄和临床结局。结论：我们提供的证据表明，SPINK 1，PRSS 1，CTRC和CFTR基因的罕见致病性变异显著影响CP的发病年龄和临床结局。还发现了广泛的基因-环境相互作用。
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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16.2
作者：
American Diabetes Association
通讯作者：
American Diabetes Association
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Cote, Gregory A.;Yadav, Dhiraj;Slivka, Adam;Hawes, Robert H.;Anderson, Michelle A.;Burton, Frank R.;Brand, Randall E.;Banks, Peter A.;Lewis, Michele D.;Disario, James A.;Gardner, Timothy B.;Gelrud, Andres;Amann, Stephen T.;Baillie, John;Money, Mary E.;O'Connell, Michael;Whitcomb, David C.;Sherman, Stuart
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Sherman, Stuart
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Jowell, PS
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Kleeff, Jorg;Whitcomb, David C.;Neoptolemos, John P.
通讯作者：
Neoptolemos, John P.
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Jalaly, Niloofar Y.;Moran, Robert A.;Singh, Vikesh K.
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Singh, Vikesh K.