本文選題：KCNJ5 + 突變��； 參考：《新疆醫(yī)科大學(xué)》2015年博士論文

【摘要】：目的:原發(fā)性醛固酮增多癥是臨床上導(dǎo)致繼發(fā)性高血壓最常見的病因之一,究其根本的原因是由于腎上腺皮質(zhì)出現(xiàn)的病變,導(dǎo)致醛固酮過多的分泌并且抑制了腎素一血管緊張素系統(tǒng)的活性的綜合征。醛固酮腺瘤與單側(cè)腎上腺增生是兩種原發(fā)性醛固酮增多癥的亞型,由于二者有著相似的臨床表型及較好的手術(shù)治療效果,對二者有無相同的發(fā)病機(jī)制,較少有研究。2011年choil等首次報(bào)道散發(fā)性醛固酮腺瘤患者有36.4%KCNJ5基因體系突變,引起該領(lǐng)域?qū)W者的廣泛關(guān)注,該研究在我國目前報(bào)道較少。了解本地區(qū)醛固酮腺瘤與單側(cè)腎上腺增生患者KCNJ5基因的突變情況以及KCNJ5基因突變后對醛固酮腺瘤與單側(cè)腎上腺增生臨床表型的影響,為進(jìn)一步探索二者的發(fā)病機(jī)制及更好的管理和控制原發(fā)性醛固酮增多癥及繼發(fā)性高血壓提供依據(jù)。方法:1)收集46例醛固酮腺瘤與14例單側(cè)腎上腺患者組織KCNJ5基因測序:①提取醛固酮腺瘤(n=46)、單側(cè)腎上腺增生(14例)患者組織的總DNA及RNA;提取相應(yīng)的患者外周血DNA作為對照;②DNA經(jīng)PCR擴(kuò)增KCNJ5基因后正反向測序,再將相應(yīng)的RNA逆轉(zhuǎn)錄為cDNA后行PCR擴(kuò)增基因正向測序,檢測上述不同組織中KCNJ5基因的序列;③獲取46例醛固酮腺瘤及14例單側(cè)腎上腺患者KCNJ5基因信息。2)收集46例醛固酮腺瘤及14例單側(cè)腎上腺患者年齡、血壓等一般臨床資料;收集電解質(zhì)、血脂等生化資料、心臟超聲以及多導(dǎo)睡眠監(jiān)測的相關(guān)指標(biāo):①分析醛固酮腺瘤患者KCNJ5基因不同突變型與臨床表現(xiàn)型之間的關(guān)系;②對比KCNJ5基因突變對二者臨床表型的影響。結(jié)果:1)46例醛固酮腺瘤與14例單側(cè)腎上腺患者組織KCNJ5基因測序結(jié)果:①46例醛固酮腺瘤與14例單側(cè)腎上腺患者組織KCNJ5基因均發(fā)現(xiàn)G151R、L168R、S209T及L102Q四個(gè)位點(diǎn)突變,其中S209T和L102Q為新的基因突變,而與其相匹配外周血的基因測序正常;國內(nèi)外尚無報(bào)道;②19.57%醛固酮腺瘤患者(9/46例)的腫瘤組織中存在p.G151R和/或p.L168R的雜合突變;21.43%單側(cè)腎上腺增生患者(3/14例)增生組織中為P.G151R或P.L168R突變,其中p.G151R突變分別是c.451GA或c.451GC,為雜合突變;③26.07%醛固酮腺瘤患者(9/46例)的腫瘤組織中存p.s209t突變,64.29%單側(cè)腎上腺增生患者(9/14例)組織中存在p.s209t突變;30.43%例醛固酮腺瘤患者(14/46例)的腫瘤組織中存p.l102q突變;71.43%單側(cè)腎上腺增生患者(10/14例)組織中存在p.l102q突變;④腎上腺醛固酮腺瘤組織中存在kcnj5基因g151r的雜合突變、l168r的突變、s209t與l102q突變,突變率為65.21%(30/46);單側(cè)腎上腺增生組織中存在kcnj5基因g151r的雜合突變、l168r的突變、s209t與l102q突變,突變率為71.43%(10/14例)。2)46例醛固酮腺瘤與14例單側(cè)腎上腺患者組織kcnj5基因突變的臨床特點(diǎn):①在apa患者中kcnj5基因突變與未突變患者比較平均收縮壓差異有統(tǒng)計(jì)學(xué)意義(p=0.042)。兩組血鉀比較差異有統(tǒng)計(jì)學(xué)意義(p=0.048),兩組在年齡、性別、醛固酮水平、腎功能、心臟超聲相關(guān)指標(biāo)比較差異無統(tǒng)計(jì)學(xué)意義(p0.05);在單側(cè)腎上腺增生患者中kcnj5基因突變與未突變患者比較平均收縮壓及舒張壓差異有統(tǒng)計(jì)學(xué)意義(p值分別為0.032和0.016)。兩組在年齡、性別、醛固酮水平、血鉀、腎功能、心臟超聲等相關(guān)指標(biāo)比較差異無統(tǒng)計(jì)學(xué)意義(p0.05);②46例醛固酮腺瘤患者中kcnj5基因g151r、l168r、s209t及l(fā)102q突變與未突變比較g151r突變較未突變組在平均收縮壓、平均舒張壓、血鉀水平、高密度脂蛋白及左室質(zhì)量指數(shù)差異有統(tǒng)計(jì)學(xué)意義(p值分別為0.005、0.003、0.023和0.004);l168r突變較未突變組在腫瘤直徑比較差異有統(tǒng)計(jì)學(xué)意義(p=0.027);s209t突變較未突變組各項(xiàng)指標(biāo)比較均差異無統(tǒng)計(jì)學(xué)意義(p0.05);l102q突變較未突變組在平均舒張壓、醛固酮水平、血鉀水平、高密度脂蛋白及射血分?jǐn)?shù)差異有統(tǒng)計(jì)學(xué)意義(p值分別為0.045、0.025、0.030、0.024和0.002);③46例醛固酮腺瘤與14例單側(cè)腎上腺增生患者kcnj5基因g151r+l168r、s209t及l(fā)102q突變比較:醛固酮腺瘤患者g151r+l168r突變較單側(cè)腎上腺增生患者在平均收縮壓、平均舒張壓及坐位醛固酮水平高,差異有統(tǒng)計(jì)學(xué)意義(p值分別為0.007、0.009和0.033);醛固酮腺瘤患者s209t突變較單側(cè)腎上腺增生患者bmi和膽醇水平高,差異有統(tǒng)計(jì)學(xué)意義(p分別為0.025和0.005);醛固酮腺瘤患者l102q突變與單側(cè)腎上腺增生患者平均舒張壓、坐位醛固酮水平、總膽固醇水平及射血分?jǐn)?shù)比較,差異有統(tǒng)計(jì)學(xué)意義(p值分別為0.022、0.027和0.033);④在46醛固酮腺瘤患者中有1例男性患者合并中度阻塞性睡眠呼吸暫停低通氣綜合征,14例單側(cè)腎上腺增生患者合并4例重度阻塞性睡眠呼吸暫停低通氣綜合征,其中3名男性,1名女性。結(jié)論:1)腎上腺醛固酮腺瘤組織中存在kcnj5基因g151r的雜合突變、l168r的突變、s209t與l102q突變,突變率為65.21%(30/46),其中s209t與l102q突變?yōu)樾掳l(fā)現(xiàn)的突變位點(diǎn),與既往的研究不同,提示kcnj5基因的突變可能與人種及地域有關(guān);2)kcnj5基因突變加重了apa患者的臨床癥狀,其中g(shù)151r突變影響最大,之后依次為l102q、l168r及s209t;3)單側(cè)腎上腺增生患者與醛固酮腺瘤存在相同KCNJ5基因G151R的雜合突變、L168R的突變、S209T與L102Q突變,突變率為71.43%(10/14),高于醛固酮腺瘤的突變率,其中S209T與L102Q為新發(fā)現(xiàn)的突變位點(diǎn),既往文獻(xiàn)尚未報(bào)到;4)KCNJ5基因突變對醛固酮腺瘤患者的臨床表型影響較單側(cè)腎上腺增生患更大,其中G151R突變影響最大,之后依次為L102Q、L168R及S209T;5)單側(cè)腎上腺增生患者與醛固酮腺瘤存在相同KCNJ5基因突變,影響程度不同,其發(fā)生機(jī)制仍需進(jìn)一步研究;6)KCNJ5基因突變是否與OSAHS的發(fā)生有關(guān),仍需進(jìn)一步的探討。
[Abstract]:Objective: primary aldosteronism is one of the most common causes of secondary hypertension. The fundamental reason is that the adrenocortical lesions are caused by the hyperaldosterone secretion and the inhibition of the renin's activity of angiotensin system. The aldosterone adenoma and unilateral adrenal hyperplasia are two. The subtype of primary aldosteronism, because the two have similar clinical phenotypes and good surgical treatment effect, there is no same pathogenesis for the two, and the first report of.2011 choil, which is the first report of sporadic aldosteronadenoma, has the mutation of the 36.4%KCNJ5 gene system, which has aroused extensive attention of the scholars in this field. At present, there are few reports in China. To understand the mutation of KCNJ5 gene in aldosterone adenoma and unilateral adrenal hyperplasia in the local area and the effect of KCNJ5 gene mutation on the clinical phenotype of aldosterone adenoma and unilateral adrenal hyperplasia in order to further explore the pathogenesis of the two and to better manage and control the primary aldosteronism. And to provide basis for secondary hypertension. Methods: 1) the KCNJ5 gene of 46 aldosterone adenomas and 14 unilateral adrenal patients was sequenced. (1) the aldosterone adenoma (n=46) was extracted, the total DNA and RNA of the tissues of the unilateral adrenal hyperplasia (14 cases) were obtained, and the corresponding peripheral blood DNA was extracted as the control; and the KCNJ5 gene was amplified by PCR by PCR. Sequence, then reverse transcription of the corresponding RNA to cDNA after PCR amplification gene sequencing to detect the sequence of KCNJ5 gene in the above different tissues; (3) to obtain 46 aldosterone adenoma and 14 cases of unilateral adrenal patients with KCNJ5 gene.2) to collect 46 aldosterone adenomas and 14 cases of unilateral adrenal patients' age, blood pressure and other general clinical data; collect electricity. Biochemical data such as degradation, blood lipid, cardiac ultrasound and polysomnography: (1) analysis of the relationship between different mutations of KCNJ5 gene in aldosterone adenoma and clinical phenotype; (2) the effect of KCNJ5 gene mutation on the clinical phenotype of two cases. Results: 46 cases of aldosterone adenoma and 14 cases of unilateral adrenal gland patients, KCNJ5 Gene sequencing results: (1) 46 aldosterone adenomas and 14 cases of unilateral adrenal patients with KCNJ5 gene were found to have four mutations in G151R, L168R, S209T and L102Q, of which S209T and L102Q were new gene mutations, and the gene sequence matched with the peripheral blood was normal; there was no report at home and abroad; (2) the swelling of the 19.57% aldosterone adenoma patients (9/46 cases) There was a heterozygous mutation of p.G151R and / or p.L168R in the tumor tissue; 21.43% the hyperplastic (3/14) patients with unilateral adrenalic hyperplasia were P.G151R or P.L168R mutations, of which p.G151R mutations were c.451GA or c.451GC, as heterozygous mutation, and (3) the tumor tissues of 26.07% aldosterone adenomas (9/46 cases) had p.s209t mutations and 64.29% unilateral adrenal glands increased. There was a p.s209t mutation in the tissue of 9/14, and p.l102q mutation in 30.43% cases of aldosterone adenoma (14/46), and p.l102q mutation in the tissues of 71.43% unilateral adrenal hyperplasia (10/14); (4) the heterozygous mutation of the kcnj5 gene g151r, the mutation of l168r, s209t and l102q process in the adrenal aldosterone adenoma tissue Mutation rate was 65.21% (30/46), and there was a heterozygous mutation of kcnj5 gene g151r in unilateral adrenal hyperplasia, l168r mutation, s209t and l102q mutation, mutation rate of 71.43% (10/14 case).2) 46 aldosterone adenomas and 14 cases of unilateral adrenal patients with kcnj5 gene mutation: (1) kcnj5 gene mutation and non mutation in APA patients The difference of the average systolic pressure was statistically significant (p=0.042). There was a significant difference between the two groups (p=0.048). There was no significant difference between the two groups in age, sex, aldosterone level, renal function, and echocardiography (P0.05). In the patients with mono adrenal hyperplasia, the kcnj5 gene mutation was compared with that of the non mutated patients. The differences in mean systolic and diastolic pressure were statistically significant (P values were 0.032 and 0.016 respectively). There was no significant difference in age, sex, aldosterone level, potassium, renal function, and cardiac ultrasound (P0.05) in two groups (P0.05); (2) the kcnj5 gene g151r, l168r, s209t and l102q mutations were compared with the non mutation in the patients with aldosterone adenoma. There was significant difference in mean systolic pressure, mean diastolic pressure, blood potassium level, high density lipoprotein and left ventricular mass index (P value 0.005,0.003,0.023 and 0.004), and the difference between l168r mutation and non mutation group was statistically significant (p=0.027), and the s209t mutation was compared with that of the non mutation group. The difference was not statistically significant (P0.05), and there was a significant difference in mean diastolic pressure, aldosterone level, blood potassium level, high density lipoprotein and ejection fraction (P value of 0.045,0.025,0.030,0.024 and 0.002), and 46 cases of aldosterone adenoma and 14 cases of unilateral adrenal hyperplasia, g151r+l168r, s209t, s209t, s209t, s209t, s209t, s209t, and s209t. Compared with the l102q mutation, the g151r+l168r mutation in the aldosterone adenoma patients was higher than that of the unilateral adrenal hyperplasia in the mean systolic pressure, the mean diastolic pressure and the sitting aldosterone level, and the difference was statistically significant (P was 0.007,0.009 and 0.033, respectively), and the s209t mutation of the aldosterone adenoma was higher than that of the unilateral adrenal hyperplasia patients with BMI and bile alcohol. The difference was statistically significant (P was 0.025 and 0.005 respectively); the difference in average diastolic blood pressure, the level of aldosterone, total cholesterol level and ejection fraction in patients with aldosterone adenoma was statistically significant (P was 0.022,0.027 and 0.033), and 1 of the 46 aldosterone adenomas were male patients. Combined with moderate obstructive sleep apnea hypopnea syndrome, 14 cases of unilateral adrenal hyperplasia combined with 4 cases of severe obstructive sleep apnea hypopnea syndrome, including 3 men and 1 women. Conclusion: 1) there is a heterozygous mutation of the kcnj5 gene g151r in the adrenal aldosterone adenoma, the mutation of l168r, the mutation of s209t and l102q, and the mutation of the adrenal aldosterone adenoma. The mutation rate was 65.21% (30/46), in which the mutation of s209t and l102q was a newly discovered mutation site, which was different from previous studies, suggesting that the mutation of the kcnj5 gene may be related to the race and region; 2) the mutation of the kcnj5 gene aggravated the clinical symptoms of the patients with APA, in which the g151r mutation was most affected, followed by l102q, l168r and s209t; 3) unilateral adrenal hyperplasia. The patients and aldosterone adenomas have the same KCNJ5 gene G151R heterozygous mutation, L168R mutation, S209T and L102Q mutation, and the mutation rate is 71.43% (10/14), which is higher than the mutation rate of aldosterone adenoma, of which S209T and L102Q are newly discovered mutation sites, the previous literature has not been reported; 4) the clinical phenotype effect of the KCNJ5 gene mutation on the aldosterone adenoma patients. More than unilateral adrenal hyperplasia, G151R mutation was most affected, followed by L102Q, L168R and S209T; 5) there was a same KCNJ5 gene mutation in the patients with unilateral adrenal hyperplasia and aldosterone adenoma. The mechanism still needs further study. 6) whether the mutation of the KCNJ5 gene is related to the occurrence of OSAHS, it still needs to be further studied. Discuss.

【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R544.1;R586.24

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