阻塞性睡眠呼吸暫停綜合癥合并高血壓患者的血壓變異性、炎癥因子特點(diǎn)及其與鋅指蛋白36基因的關(guān)聯(lián)研究
發(fā)布時(shí)間：2018-09-10 18:43
【摘要】：目的：(1)探討阻塞性睡眠呼吸暫停綜合癥(OSAHS)合并高血壓患者的血壓變異(BPV)情況；OSAHS合并高血壓患者心臟、外周血管及腎臟受損情況及與BPV的相關(guān)性。(2)探討OSAHS合并高血壓患者與腫瘤壞死因子-α (TNF-α)、白介素-6(IL-6)的相關(guān)性。(3)探討OSAHS合并高血壓患者與TNF-α、IL-6及ZFP36基因多態(tài)性的關(guān)聯(lián)性。方法：第一部分：采用病例對(duì)照研究,共入選住院OSAHS合并高血壓患者583例,按睡眠呼吸暫停低通氣指數(shù)(AHI)將患者分成輕度OSAHS組、中度OSAHS組及重度OSAHS組；同期住院?jiǎn)渭兏哐獕夯颊邽閷?duì)照組,所有患者行PSG監(jiān)測(cè)、動(dòng)態(tài)血壓監(jiān)測(cè)、心臟超聲檢查、頸動(dòng)脈超聲檢查及相關(guān)生化指標(biāo)檢測(cè)。對(duì)收集的資料進(jìn)行相關(guān)統(tǒng)計(jì)分析。第二部分及第三部分：采用病例對(duì)照研究,其中共確診OSAHS合并高血壓患者653例,將其分為輕度OSAHS組245例,年齡為47.16±10.18歲；中度OSAHS組195例,年齡為48.99±9.75歲；重度OSAHS組213例,年齡為48.09±9.45歲。同期住院的單純高血壓患者共243例,年齡為43.59±8.94歲。正常對(duì)照組選自健康體檢者共326例。年齡為58.76±8.87歲。對(duì)上述病例進(jìn)行病史采集、人體學(xué)指標(biāo)測(cè)定、血脂、血糖等生化指標(biāo)檢測(cè),并采用放免法對(duì)所有病例進(jìn)行TNF-α、IL-6檢測(cè)。將TNF-a及IL-6與OSAHS相關(guān)危險(xiǎn)因素進(jìn)行相關(guān)分析,并對(duì)影響AHI的可能因素進(jìn)行多重線性回歸分析。第四部分:病例來源同第二部分,其中1089例進(jìn)行鋅指蛋白36(ZFP36)基因分型,ZFP36基因SNP的選擇采用標(biāo)簽SNP策略,對(duì)篩選出的ZFP36rs251846(-194AG)、rs3746083(1181CT)及rs17879933(2436-/T)與OSAHS的關(guān)系進(jìn)行統(tǒng)計(jì)分析。結(jié)果：第一部分:四組之間的血壓變異性(BPV)差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。白天收縮壓變異性、夜間收縮壓均值、夜間收縮壓變異性、夜間舒張壓均值、夜間舒張壓變異性、夜間收縮壓下降率對(duì)AHI有影響。室間隔厚度、左心室后壁厚度、左心室質(zhì)量指數(shù)及左心室舒張末期容積隨AHI的嚴(yán)重程度增加而增加(P0.05),并且受BPV不同指標(biāo)影響。左、右側(cè)頸總動(dòng)脈內(nèi)膜中層厚度隨OSAHS合并高血壓患者隨AHI嚴(yán)重程度的增加而增加(P0.05),動(dòng)脈硬化斑塊的檢出率增加(P0.05)。BPV對(duì)平均頸動(dòng)脈內(nèi)膜中層厚度有影響。白天收縮壓負(fù)荷值為OSHAS合并高血壓患者頸動(dòng)脈粥樣硬化斑塊形成的獨(dú)立危險(xiǎn)因素。OSAHS合并高血壓患者的血尿酸及24h尿蛋白定量在四組之間存在統(tǒng)計(jì)學(xué)差異(P0.05)。內(nèi)生肌酐清除率隨在四組之間無統(tǒng)計(jì)學(xué)差異,但BPV對(duì)OSAHS合并高血壓患者的血尿酸、24h尿蛋白定量及內(nèi)生肌酐清除率有影響。第二部分及第三部分：OSAHS合并高血壓患者的TNF-α水平與腹圍、BMI、DBP呈正相關(guān)(P0.05),與HDL-C呈負(fù)相關(guān)(P0.05)。IL-6水平與腹圍、BMI呈正相關(guān)(P0.05)。OSAHS合并高血壓患者的TNF-α及IL-6與AHI、ODI4、Time with SaO290%及TRTSaO290%均呈正相關(guān)關(guān)系(P0.05),而與最低SaO2及平均SaO2呈負(fù)線性相關(guān)關(guān)系(P0.05)。多重線性回歸分析發(fā)現(xiàn)腹圍、TNF-α及IL-6對(duì)OSAHS合并高血壓患者AHI的嚴(yán)重程度有影響。第四部分:ZFP36基因rs251846(-194AG)及rs17879933(2436-/T)位點(diǎn)基因型及等位基因頻率分布在OSAHS合并高血壓患者、單純高血壓患者及正常對(duì)照組之間存在差異(P0.05),但ZFP36基因rs3746083(1181CT)位點(diǎn)基因型及等位基因頻率分布中未發(fā)現(xiàn)差異(P0.05)。按性別分層后,男性的ZFP36rs251846、rs17879933及rs3746083位點(diǎn)的基因型及等位基因頻率分布中均未發(fā)現(xiàn)差異(P0.05)。女性的ZFP36rs251846及rs3746083位點(diǎn)的基因型及等位基因頻率分布中存在差異(P0.05)。ZFP36rs251864位點(diǎn)在腹圍、BMI、TG、TNF-α及IL-6之間存在差異(P0.05)。ZFP36rs17879933位點(diǎn)在腹圍、BMI及TNF-α之間存在差異(P0.05)。而ZFP36rs3746083位點(diǎn)無論是炎癥因子,還是表型資料中均未發(fā)現(xiàn)差異。按性別分層后,男性腹圍及TNF-α在ZFP36rs251864位點(diǎn)存在差異(P0.05)；男性尿酸及TNF-α在ZFP36rs17879933位點(diǎn)存在差異(P0.05)。女性BMI、TNF-α及IL-6在ZFP36rs251846及rs3746083位點(diǎn)均有差異(P0.05)。ZFP36rs251846、 rs17879933及rs3746083位點(diǎn)的呼吸睡眠暫停監(jiān)測(cè)指標(biāo)之間無差異,即使是在進(jìn)行性別分層后。Logistic回歸分析表明腹圍及FPG是OSAHS的獨(dú)立危險(xiǎn)因素。TNF-α、IL-6及ZFP36不是OSAHS的獨(dú)立危險(xiǎn)因素。結(jié)論：第一部分：OSAHS合并高血壓患者隨AHI的嚴(yán)重程度BPV變化明顯。OSAHS合并高血壓患者隨AHI嚴(yán)重程度的增加,心臟、外周血管及腎功能受損程度存在差異,同時(shí)受BPV影響。第二部分及第三部分:腹圍、TNF-α及IL-6影響OSAHS合并高血壓患者AHI的嚴(yán)重程度。第四部分：ZFP36基因rs251846、rs3746083及rs17879933位點(diǎn)在OSAHS合并高血壓在女性患者存在差異。ZFP36基因rs251846、rs3746083及rs17879933位點(diǎn)的多態(tài)性參與OSAHS合并高血壓患者TNF-α、IL-6的調(diào)節(jié),但與OSAHS的患病可能無關(guān)。
[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.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R544.1;R766
本文編號(hào)：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.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R544.1;R766
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