SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan
SPINK1, ADH2, and ALDH2 gene variants and alcoholic chronic pancreatitis in Japan
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DOI：
10.1111/j.1440-1746.2007.05291.x
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发表时间：
2008-03-01
影响因子：
4.1
通讯作者：
Masamune, Atsushi
中科院分区：
文献类型：
--
作者：
Shimosegawa, Tooru;Kume, Kiyoshi;Masamune, Atsushi
丝氨酸蛋白酶抑制剂Kazal 1型（SPINK 1）是一种有效的抗蛋白酶和胰内胰蛋白酶活性的重要失活因子。SPINK 1突变导致的功能丧失导致抑制能力降低。SPINK 1突变在日本酒精性慢性胰腺炎（CP）中的意义及其功能作用尚不清楚。本研究的目的是阐明日本CP患者中SPINK 1、乙醇脱氢酶2（ADH 2）和乙醛脱氢酶2（ALDH 2）变异体的发生率。186例CP患者和527例健康志愿者入选。突变分析采用聚合酶链反应-限制性片段长度多态性和直接测序。用放射免疫法测定血清胰分泌型胰蛋白酶抑制剂（PSTI）水平。非酒精性CP患者SPINK 1区N34 S和IVS 3 + 2 T> C的频率（分别为12.9%和8.6%）显著高于正常对照组（0.37%和0%）。总的来说，93例非酒精性CP患者中有18例（19.4%）至少有一个SPINK 1突变。关于酒精性CP，我们在少数患者（3.9%）中发现IVS 3 + 2 T> c。IVS 3 + 2 T> C突变患者的血清PSTI浓度降低。酒精性CP组ADH 2 *2等位基因频率显著高于无胰腺炎的酒精性CP组。与健康对照组相比，酒精性CP患者ALDH 2 *2等位基因的频率显著降低。总之，SPINK 1突变与非酒精性CP相关。此外，我们发现IVS 3 + 2 T> C突变患者的野生型PSTI数量减少。酒精代谢酶的变异出现在酒精CP的关系。
The serine protease inhibitor Kazal type 1 (SPINK1) is a potent antiprotease and an important inactivation factor of intrapancreatic trypsin activity. Loss of function by the SPINK1 mutations leads to decreased inhibitory capacity. The significance of SPINK1 mutations in alcoholic chronic pancreatitis (CP) in Japan and its functional role remain unclear. The aim of the present study was to clarify the incidence of SPINK1, alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) variants in CP patients in Japan. One hundred and 86 patients with CP, and 527 healthy volunteers were enrolled. Mutational analyses were performed by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. Serum pancreatic secretory trypsin inhibitor (PSTI) level was measured by radioimmunoassay. The frequencies of N34S and IVS3 + 2T > C in the SPINK1 gere were significantly higher in patients with non-alcoholic CP (12.9% and 8.6%, respectively) than in normal subjects (0.37% and 0%). In total, 18 of 93 (19.4%) patients with non-alcoholic CP had at least one SPINK1 mutation. Concerning alcoholic CP, we found IVS3 + 2T> c in a small number of patients (3.9%). Serum PSTI concentration was decreased in patients with the IVS3 + 2T > C mutation. The frequency of the ADH2*2 allele in the alcoholic CP group was significantly higher than that in alcoholics without pancreatitis. The frequency of the ALDH2*2 allele was significantly low in patients with alcoholic CP compared with healthy controls. In conclusion, SPINK1 mutations were associated with non-alcoholic CP. Furthermore, we revealed the amount of wild-type PSTI was decreased in patients with IVS3 + 2T > C mutation. Variants of alcohol-metabolizing enzymes appeared in the relation to alcoholic CP.