SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis
SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis
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DOI：
10.1053/gast.2000.18017
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发表时间：
2000-09-01
期刊：
影响因子：
29.4
通讯作者：
Whitcomb, DC
中科院分区：
文献类型：
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作者：
Pfützer, RH;Barmada, MM;Whitcomb, DC
背景和目的：功能获得性胰蛋白酶突变导致急性胰腺炎和慢性胰腺炎。胰蛋白酶抑制剂功能的丧失可能会产生类似的影响。我们调查了家族性胰腺炎、特发性慢性胰腺炎和对照中 SPINK1 (PSTI) 突变的患病率。方法：在 5 个熟悉的胰腺炎家族中进行遗传连锁研究。对 112 名受影响个体和 95 份对照 DNA 样本的整个 SPINK1 基因进行了测序，并对另外 95 份对照的外显子 3 进行了测序。进行了基于 X 射线晶体学的模型构建和统计研究。结果：排除了胰腺炎与 5q31.1-2 之间的显着关联。鉴定出新的 SPINK1 突变、1 个 D50E 突变、1 个 IVS3+125 C>A 和 5 个 IVS3+184 T>A 内含子多态性。在 112 名患者中，有 29 名 (25%) 观察到 N34S 和 P55S 突变，分别为 N34S/N34S (n = 7)、N34S/wt (n = 19)、N34S/P55S (n = 2) 和 N34S/D50E (n = 1)。 380 个对照等位基因显示 3 个 N34S (0.77%)、2 个 P55S (0.53%)，并且没有 D50E 突变。纯合子和杂合子患者的发病年龄和严重程度相似。结构模型揭示了 N34S 突变的几种可能的病理生理机制。结论：SPINK1 突变在人群中很常见（约 2%），但与胰腺炎明显相关。突变相关的风险很低。建模和家族聚类表明，SPINK1 突变可能通过降低其他遗传或环境因素引发胰腺炎的阈值来改变疾病，但其本身不会引起疾病。
Background & Aims: Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. Methods: Genetic-linkage studies were performed in 5 familiar pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography- based model building and statistical studies were performed. Results: Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. Conclusions: SPINK1 mutations are common in the population (similar to 2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.