醛固酮瘤组织体细胞KCNJ5基因错义突变与原发性醛固酮增多症的相关性研究

Association of KCNJ5 gene missense mutations with aldosterone-producing adenoma and primary hyperaldosteronism

目的 检测原发性醛固酮增多症醛固酮瘤组织中体细胞KCNJ5基因错义突变情况,观察其错义突变与原发性醛固酮增多症患者临床表型之间的关系。方法 收集新疆自治区人民医院高血压诊疗中心诊断并经过手术和病理诊断证实的醛固酮瘤患者的临床资料和组织标本46例,同时收集患者外周血标本作为对照,应用PCR技术和DNA直接测序的方法检测所有标本的KCNJ5基因,比较组织细胞与外周血细胞基因错义突变的不同,并分析其基因型与临床表型之间的联系。结果 46例醛固酮瘤组织中发现3种错义突变：c.451G〉C/A（p.G151R）（5/46）,c.503T〉G（p.L168R）（4/46）,c.830T〉A（p.S209T）（12/46）。其中c.830T〉A（p.S209T）为之前未报到突变。所有患者外周血中均未检测出错义突变。比较组织细胞基因突变型与野生型性别、年龄、收缩压、舒张压、高血压病程、血K＋、24h尿K＋、肿瘤直径、醛固酮、血浆肾素活性、醛固酮肾素活性比值和家族史阳性比例等临床表型,发现G151R、L168R、S209T组间收缩压和血K＋水平差异有统计学意义,G151R组收缩压明显高于其他2组,而血K＋则显著低于另2组。结论 46例醛固酮瘤组织中发现3种错义突变,分析其基因型与临床表型之间的联系提示KCNJ5基因错义突变与原发性醛固酮增多症的发病相关,原发性醛固酮增多症可能存在其他与目前不同的亚型。

Objective This study is about to detect the KCNJ5 gene variations in aldosterone-producing adenoma （APA） with primary hyperaldosteronism （PA）,and to investigate the association of the KCNJ5 gene missense mutations with APA and PA. Methods A total of 46 APA tumors and their clinical characteristics were collected from Hypertension Center of the People′s Hospital of Xinjiang Uygur Autonomous Region, and all the tumors were confirmed by pathology. All the samples of the coding region segments of KCNJ5 were detected by PCR and direct DNA sequencing to compare the different missense mutations in the tumor cells and peripheral blood cells and to analyze the association between the genotype and phenotype. Results Three missense mutations were found in 46 patients with APA： c.451G〉C/A （p.G151R）（5/46）,c.503T〉G（p.L168R） （4/46）, c.830T〉A（p.S209T）（12/46）. S209T, as an unreported somatic mutation was observed. There were no missense mutations detected in the peripheral blood. Sex, age, systolic blood pressure, diastolic blood pressure, duration of hypertension, plasma potassium, urine potassium, aldosterone, plasma renin activity, aldosterone, and plasma renin activity ratio, as well as the rate of positive family history were compared between the mutants and wild-types. Systolic blood pressure and plasma potassium level among G151R, L168R, and S209T had statistical differences. Systolic blood pressure in G151R was significantly higher than the other two groups, while the plasma potassium level was significantly lower than the other groups. Conclusions Three missense mutations were found in 46 patients with APA. The subjects with mutations had more serious condition than those without mutations after comparing their clinical phenotype. Besides, other different subtypes may exist in PA.