阻塞性睡眠呼吸暂停综合症合并高血压患者的血压变异性、炎症因子特点及其与锌指蛋白36基因的关联研究
发布时间：2018-09-10 18:43
【摘要】：目的：(1)探讨阻塞性睡眠呼吸暂停综合症(OSAHS)合并高血压患者的血压变异(BPV)情况；OSAHS合并高血压患者心脏、外周血管及肾脏受损情况及与BPV的相关性。(2)探讨OSAHS合并高血压患者与肿瘤坏死因子-α (TNF-α)、白介素-6(IL-6)的相关性。(3)探讨OSAHS合并高血压患者与TNF-α、IL-6及ZFP36基因多态性的关联性。方法：第一部分：采用病例对照研究,共入选住院OSAHS合并高血压患者583例,按睡眠呼吸暂停低通气指数(AHI)将患者分成轻度OSAHS组、中度OSAHS组及重度OSAHS组；同期住院单纯高血压患者为对照组,所有患者行PSG监测、动态血压监测、心脏超声检查、颈动脉超声检查及相关生化指标检测。对收集的资料进行相关统计分析。第二部分及第三部分：采用病例对照研究,其中共确诊OSAHS合并高血压患者653例,将其分为轻度OSAHS组245例,年龄为47.16±10.18岁；中度OSAHS组195例,年龄为48.99±9.75岁；重度OSAHS组213例,年龄为48.09±9.45岁。同期住院的单纯高血压患者共243例,年龄为43.59±8.94岁。正常对照组选自健康体检者共326例。年龄为58.76±8.87岁。对上述病例进行病史采集、人体学指标测定、血脂、血糖等生化指标检测,并采用放免法对所有病例进行TNF-α、IL-6检测。将TNF-a及IL-6与OSAHS相关危险因素进行相关分析,并对影响AHI的可能因素进行多重线性回归分析。第四部分:病例来源同第二部分,其中1089例进行锌指蛋白36(ZFP36)基因分型,ZFP36基因SNP的选择采用标签SNP策略,对筛选出的ZFP36rs251846(-194AG)、rs3746083(1181CT)及rs17879933(2436-/T)与OSAHS的关系进行统计分析。结果：第一部分:四组之间的血压变异性(BPV)差异具有统计学意义(P0.05)。白天收缩压变异性、夜间收缩压均值、夜间收缩压变异性、夜间舒张压均值、夜间舒张压变异性、夜间收缩压下降率对AHI有影响。室间隔厚度、左心室后壁厚度、左心室质量指数及左心室舒张末期容积随AHI的严重程度增加而增加(P0.05),并且受BPV不同指标影响。左、右侧颈总动脉内膜中层厚度随OSAHS合并高血压患者随AHI严重程度的增加而增加(P0.05),动脉硬化斑块的检出率增加(P0.05)。BPV对平均颈动脉内膜中层厚度有影响。白天收缩压负荷值为OSHAS合并高血压患者颈动脉粥样硬化斑块形成的独立危险因素。OSAHS合并高血压患者的血尿酸及24h尿蛋白定量在四组之间存在统计学差异(P0.05)。内生肌酐清除率随在四组之间无统计学差异,但BPV对OSAHS合并高血压患者的血尿酸、24h尿蛋白定量及内生肌酐清除率有影响。第二部分及第三部分：OSAHS合并高血压患者的TNF-α水平与腹围、BMI、DBP呈正相关(P0.05),与HDL-C呈负相关(P0.05)。IL-6水平与腹围、BMI呈正相关(P0.05)。OSAHS合并高血压患者的TNF-α及IL-6与AHI、ODI4、Time with SaO290%及TRTSaO290%均呈正相关关系(P0.05),而与最低SaO2及平均SaO2呈负线性相关关系(P0.05)。多重线性回归分析发现腹围、TNF-α及IL-6对OSAHS合并高血压患者AHI的严重程度有影响。第四部分:ZFP36基因rs251846(-194AG)及rs17879933(2436-/T)位点基因型及等位基因频率分布在OSAHS合并高血压患者、单纯高血压患者及正常对照组之间存在差异(P0.05),但ZFP36基因rs3746083(1181CT)位点基因型及等位基因频率分布中未发现差异(P0.05)。按性别分层后,男性的ZFP36rs251846、rs17879933及rs3746083位点的基因型及等位基因频率分布中均未发现差异(P0.05)。女性的ZFP36rs251846及rs3746083位点的基因型及等位基因频率分布中存在差异(P0.05)。ZFP36rs251864位点在腹围、BMI、TG、TNF-α及IL-6之间存在差异(P0.05)。ZFP36rs17879933位点在腹围、BMI及TNF-α之间存在差异(P0.05)。而ZFP36rs3746083位点无论是炎症因子,还是表型资料中均未发现差异。按性别分层后,男性腹围及TNF-α在ZFP36rs251864位点存在差异(P0.05)；男性尿酸及TNF-α在ZFP36rs17879933位点存在差异(P0.05)。女性BMI、TNF-α及IL-6在ZFP36rs251846及rs3746083位点均有差异(P0.05)。ZFP36rs251846、 rs17879933及rs3746083位点的呼吸睡眠暂停监测指标之间无差异,即使是在进行性别分层后。Logistic回归分析表明腹围及FPG是OSAHS的独立危险因素。TNF-α、IL-6及ZFP36不是OSAHS的独立危险因素。结论：第一部分：OSAHS合并高血压患者随AHI的严重程度BPV变化明显。OSAHS合并高血压患者随AHI严重程度的增加,心脏、外周血管及肾功能受损程度存在差异,同时受BPV影响。第二部分及第三部分:腹围、TNF-α及IL-6影响OSAHS合并高血压患者AHI的严重程度。第四部分：ZFP36基因rs251846、rs3746083及rs17879933位点在OSAHS合并高血压在女性患者存在差异。ZFP36基因rs251846、rs3746083及rs17879933位点的多态性参与OSAHS合并高血压患者TNF-α、IL-6的调节,但与OSAHS的患病可能无关。
[Abstract]:Objective: (1) To investigate the blood pressure variability (BPV) in patients with obstructive sleep apnea syndrome (OSAHS) and hypertension, the damage of heart, peripheral blood vessels and kidneys in patients with OSAHS and hypertension, and the correlation with BPV. (2) To explore the relationship between OSAHS and hypertension, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6). 3) To investigate the association between TNF-alpha, IL-6 and ZFP36 gene polymorphisms in patients with OSAHS and hypertension. Methods: A case-control study was conducted in 583 hospitalized patients with OSAHS and hypertension. The patients were divided into mild OSAHS, moderate OSAHS and severe OSAHS groups according to sleep apnea hypopnea index (AHI). Patients with simple hypertension were treated with PSG monitoring, ambulatory blood pressure monitoring, cardiac ultrasonography, carotid ultrasonography and related biochemical indexes. The collected data were analyzed statistically. Part two and part three: A case-control study was conducted in 653 patients with OSAHS and hypertension. 245 patients were divided into mild OSAHS group, aged 47.16 + 10.18 years; 195 patients in moderate OSAHS group, aged 48.99 + 9.75 years; 213 patients in severe OSAHS group, aged 48.09 + 9.45 years. All cases were examined for TNF-a and IL-6 by radioimmunoassay. Correlation analysis was made between TNF-a and IL-6 and OSAHS-related risk factors, and multiple linear regression analysis was made for the possible factors affecting AHI. One hundred and eighty-nine of them were genotyped for zinc finger protein 36 (ZFP36). The SNP of ZFP36 gene was selected by labeled SNP strategy. The relationship between selected ZFP36 rs251846 (-194AG), rs3746083 (1181CT), rs17879933 (2436 -/T) and OSAHS was statistically analyzed. 5) Variability of systolic blood pressure in the daytime, mean of nocturnal systolic blood pressure, mean of nocturnal diastolic blood pressure, variability of nocturnal diastolic blood pressure, and decrease rate of nocturnal systolic blood pressure have influence on AHI. The intima-media thickness of left and right common carotid artery increased with the severity of OSAHS and hypertension (P 0.05), and the detection rate of atherosclerotic plaque increased (P 0.05). BPV had an effect on the mean intima-media thickness of carotid artery. There were significant differences in serum uric acid and 24-hour urinary protein among the four groups (P 0.05). There was no significant difference in endogenous creatinine clearance between the four groups, but BPV had significant effects on serum uric acid, 24-hour urinary protein and endogenous creatinine clearance in OSAHS patients with hypertension. Part 2 and Part 3: TNF-a levels in OSAHS patients with hypertension were positively correlated with abdominal circumference, BMI, DBP (P 0.05), and negatively correlated with HDL-C (P 0.05). IL-6 levels were positively correlated with abdominal circumference and BMI (P 0.05). TNF-a and IL-6 levels in OSAHS patients with hypertension were positively correlated with AHI, ODI 4, Time with SaO2 90% and TRTSaO2 90% (P 0.05). Multiple linear regression analysis showed that abdominal circumference, TNF-a and IL-6 had an effect on the severity of AHI in OSAHS patients with hypertension. Part IV: The genotype and allele frequencies of ZFP36 gene rs251846 (-194AG) and rs17879933 (2436 -/T) were distributed in OSAHS patients with hypertension. There was no significant difference in genotype and allele frequency distribution of ZFP36 gene rs3746083 (1181CT) locus (P 0.05). Gender stratification revealed no difference in genotype and allele frequency distribution of ZFP36 rs251846, rs17879933 and rs3746083 loci in men (P 0.05). Genotype and allele frequencies of ZFP36rs251846 and rs3746083 were different in women (P 0.05). ZFP36rs251864 was different in abdominal circumference, BMI, TG, TNF-alpha and IL-6 (P 0.05). ZFP36rs17879933 was different in abdominal circumference, BMI and TNF-alpha (P 0.05). ZFP36rs3746083 was different in inflammatory factors. After sex stratification, there were differences in male abdominal circumference and TNF-alpha at ZFP36rs251864 (P 0.05); in male uric acid and TNF-alpha at ZFP36rs17879933 (P 0.05). There were differences in BMI, TNF-alpha and IL-6 at ZFP36rs251846 and rs3746083 (P 0.05). Logistic regression analysis showed that abdominal circumference and FPG were independent risk factors for OSAHS. TNF-a, IL-6 and ZFP36 were not independent risk factors for OSAHS. CONCLUSION: Part I: BPV in OSAHS patients with hypertension changed significantly with the severity of AHI. The severity of AHI in patients with OSAHS and hypertension was affected by BPV. Part 2 and Part 3: Abdominal circumference, TNF-a and IL-6 affected the severity of AHI in patients with OSAHS and hypertension. Part 4: ZFP36 gene rs251846, rs3746083 and rs17879933 in OSAH. ZFP36 gene rs251846, rs3746083 and rs17879933 polymorphisms are involved in the regulation of TNF-a and IL-6 in OSAHS patients with hypertension, but may not be associated with OSAHS.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R544.1;R766
本文编号：2235292
[Abstract]:Objective: (1) To investigate the blood pressure variability (BPV) in patients with obstructive sleep apnea syndrome (OSAHS) and hypertension, the damage of heart, peripheral blood vessels and kidneys in patients with OSAHS and hypertension, and the correlation with BPV. (2) To explore the relationship between OSAHS and hypertension, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6). 3) To investigate the association between TNF-alpha, IL-6 and ZFP36 gene polymorphisms in patients with OSAHS and hypertension. Methods: A case-control study was conducted in 583 hospitalized patients with OSAHS and hypertension. The patients were divided into mild OSAHS, moderate OSAHS and severe OSAHS groups according to sleep apnea hypopnea index (AHI). Patients with simple hypertension were treated with PSG monitoring, ambulatory blood pressure monitoring, cardiac ultrasonography, carotid ultrasonography and related biochemical indexes. The collected data were analyzed statistically. Part two and part three: A case-control study was conducted in 653 patients with OSAHS and hypertension. 245 patients were divided into mild OSAHS group, aged 47.16 + 10.18 years; 195 patients in moderate OSAHS group, aged 48.99 + 9.75 years; 213 patients in severe OSAHS group, aged 48.09 + 9.45 years. All cases were examined for TNF-a and IL-6 by radioimmunoassay. Correlation analysis was made between TNF-a and IL-6 and OSAHS-related risk factors, and multiple linear regression analysis was made for the possible factors affecting AHI. One hundred and eighty-nine of them were genotyped for zinc finger protein 36 (ZFP36). The SNP of ZFP36 gene was selected by labeled SNP strategy. The relationship between selected ZFP36 rs251846 (-194AG), rs3746083 (1181CT), rs17879933 (2436 -/T) and OSAHS was statistically analyzed. 5) Variability of systolic blood pressure in the daytime, mean of nocturnal systolic blood pressure, mean of nocturnal diastolic blood pressure, variability of nocturnal diastolic blood pressure, and decrease rate of nocturnal systolic blood pressure have influence on AHI. The intima-media thickness of left and right common carotid artery increased with the severity of OSAHS and hypertension (P 0.05), and the detection rate of atherosclerotic plaque increased (P 0.05). BPV had an effect on the mean intima-media thickness of carotid artery. There were significant differences in serum uric acid and 24-hour urinary protein among the four groups (P 0.05). There was no significant difference in endogenous creatinine clearance between the four groups, but BPV had significant effects on serum uric acid, 24-hour urinary protein and endogenous creatinine clearance in OSAHS patients with hypertension. Part 2 and Part 3: TNF-a levels in OSAHS patients with hypertension were positively correlated with abdominal circumference, BMI, DBP (P 0.05), and negatively correlated with HDL-C (P 0.05). IL-6 levels were positively correlated with abdominal circumference and BMI (P 0.05). TNF-a and IL-6 levels in OSAHS patients with hypertension were positively correlated with AHI, ODI 4, Time with SaO2 90% and TRTSaO2 90% (P 0.05). Multiple linear regression analysis showed that abdominal circumference, TNF-a and IL-6 had an effect on the severity of AHI in OSAHS patients with hypertension. Part IV: The genotype and allele frequencies of ZFP36 gene rs251846 (-194AG) and rs17879933 (2436 -/T) were distributed in OSAHS patients with hypertension. There was no significant difference in genotype and allele frequency distribution of ZFP36 gene rs3746083 (1181CT) locus (P 0.05). Gender stratification revealed no difference in genotype and allele frequency distribution of ZFP36 rs251846, rs17879933 and rs3746083 loci in men (P 0.05). Genotype and allele frequencies of ZFP36rs251846 and rs3746083 were different in women (P 0.05). ZFP36rs251864 was different in abdominal circumference, BMI, TG, TNF-alpha and IL-6 (P 0.05). ZFP36rs17879933 was different in abdominal circumference, BMI and TNF-alpha (P 0.05). ZFP36rs3746083 was different in inflammatory factors. After sex stratification, there were differences in male abdominal circumference and TNF-alpha at ZFP36rs251864 (P 0.05); in male uric acid and TNF-alpha at ZFP36rs17879933 (P 0.05). There were differences in BMI, TNF-alpha and IL-6 at ZFP36rs251846 and rs3746083 (P 0.05). Logistic regression analysis showed that abdominal circumference and FPG were independent risk factors for OSAHS. TNF-a, IL-6 and ZFP36 were not independent risk factors for OSAHS. CONCLUSION: Part I: BPV in OSAHS patients with hypertension changed significantly with the severity of AHI. The severity of AHI in patients with OSAHS and hypertension was affected by BPV. Part 2 and Part 3: Abdominal circumference, TNF-a and IL-6 affected the severity of AHI in patients with OSAHS and hypertension. Part 4: ZFP36 gene rs251846, rs3746083 and rs17879933 in OSAH. ZFP36 gene rs251846, rs3746083 and rs17879933 polymorphisms are involved in the regulation of TNF-a and IL-6 in OSAHS patients with hypertension, but may not be associated with OSAHS.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R544.1;R766
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