【作者】 梁燕；

【导师】 平芬；

【作者基本信息】 河北医科大学 ， 内科学， 2008， 硕士

【摘要】 目的:探讨血管紧张素Ⅱ-1型受体(AT1-R)的基因A1166/C多态性与阻塞性睡眠呼吸暂停低通气综合征(obstructive sleep apnea-hypopnea syndrome,OSAHS)及睡眠呼吸暂停低通气综合征合并高血压(OSAHS and Hypertension)的相关性。旨在寻找与单纯OSAHS及OSAHAHT发生的有关基因型,并研究这种基因多态性在OSAHS和OSAHAHT的发病和病情进展中的作用。方法:随机选择OSAHS患者65例(其中男性38人,女性27人),所有患者均有夜间睡眠中打鼾、呼吸暂停及白天嗜睡病史,并经多导睡眠图(polysomnography,PSG)监测确诊,OSAHS的诊断依据中华医学会呼吸病学分会睡眠呼吸疾病学组制定的诊断标准[1],即睡眠呼吸暂停低通气指数(apnea hypopnea index AHI,平均每小时睡眠中的呼吸暂停加上低通气次数)≥5次/h。呼吸暂停指睡眠过程中口鼻呼吸气流均停止10s以上,低通气指睡眠过程中呼吸气流强度较基础水平降低50%以上并伴有血氧饱和度较基础水平下降≥4%。其中无并发症的单纯OSAHS患者31例,年龄32～71(47.5±10.3)岁,体重指数23.04～33.61 (28.68±3.16 )kg/m2。OSAHAHT患者34例,年龄32～76 (52.55±12.74)岁,体重指数26.12～39.79 (29.48±3.89) kg/m2,符合OSAHS诊断标准,并达到《2004年中国高血压防治指南》[2]高血压诊断标准,高血压发生晚于OSAHS,且排除肾源性、内分泌性等继发性高血压原因;对照组70例(其中男性40例,女性30例),年龄26～55岁(47.65±8.07),体重指数21.67～29.76 (27.13±2.14) kg/m2,经询问病史及行Stardust便携式睡眠监测仪初筛检查,排除OSAHS。比较三组间年龄和体重指数无显著性差异(均p>0.05),并除外了继发性性高血压和缺血性心脏病等干扰因素。所有入选者在睡眠呼吸监测结束,晨醒5分钟内抽取空腹静脉血5ml,分别应用酚-氯仿法提取DNA再用聚合酶链反应(PCR法)扩增DNA片段,用限制性内切酶酶切,电泳分型法检测AT1R基因A1166/C多态性。三组基因型AA、AC、CC比较采用卡方检验,单纯OSAHS与OSAHAHT患者的睡眠呼吸监测指标比较采用t检验。结果:1.正常人群中AT1R基因AA、AC、CC型的分布频率分别为88.2%、10.3%、1.5%,OSAHS患者的基因频率分别为72.3%、26.3%、1.4%,OSAHS患者与对照组比较其构成有显著性差异(χ2=5.733,P<0.05)。正常人群中A和C等位基因频率分别为93%和7% ,OSAHS患者的等位基因频率分别为85%和15%两组相比有显著性差异(χ2=4.861 P<0.05)。单纯OSAHS患者等位基因A和C的频率分别为62%和38%。OSAHS合并高血压患者分别为80%和20%。其分布有显著性差异。(χ2=5.355 P<0.05)2.OSAHAHT患者组与单纯OSAHS患者组比较,OSAHAHT患者组AT1R基因AA、AC、CC型的分布频率分别为71%、29%、0%,单纯OSAHS患者组AT1R基因AA、AC、CC型的分布频率分别为74%、23%、3%, OSAHAHT患者组与单纯OSAHS患者组比较其构成无显著性差异(χ2=0.105,P>0.05)。OSAHAHT患者组A和C等位基因频率分别为80%和20%,单纯OSAHS患者组A和C等位基因频率分别为62%和38%,OSAHAHT患者组与单纯OSAHS患者组比较其构成有显著性差异(χ2=5.355,P<0.05)。且OSAHAHT患者组与单纯OSAHS患者组比较,其中A的等位基因频率明显高于C的等位基因频率。3、与单纯OSAHS患者比较,OSAHAHT患者的睡眠呼吸监测指标AHI、平均SaO2,平均呼吸暂停时间,均有统计学差异(t分别为0.7567,0.54,2.2615;p<0.05,p<0.05,p<0.05),而最长呼吸暂停时间、最低氧饱和度、SaO2<90%的时间,在两组间无统计学差异(均为p>0.05)。4.AA、AC、CC三种不同基因型的OSAHS患者的睡眠呼吸监测指标比较,三种基因型的AHI、平均呼吸暂停时间、SaO2<90%的时间、最低SaO2和快动眼睡眠占总睡眠时间百分比(REM/TST)均有统计学差异(p<0.05)。而三种不同基因型的睡眠呼吸障碍时的最长呼吸暂停时间无明显差异(p>0.05)。结论: 1.OSAHS的发病与AT1R基因A/C多态性相关联。单纯OSAHS及OSAHAHT患者中AC+CC基因型频率显著高于正常对照组。并且1166C等位基因频率显著高于正常对照组。单纯OSAHS与OSAHAHT患者相比,A和C的等位基因频率有显著差异性。2.AC及CC基因型的OSAHS患者睡眠呼吸暂停低通气指数(AHI)、平均呼吸暂停时间,最低血氧饱和度均与AA基因型患者差异有统计学意义。因此OSAHS的发病与AT1R基因A/C多态性相关联,基因型AC和等位基因C可能是OSAHS发病的危险因素。更多还原

【Abstract】 Objectives: To investigate the association of AT1R A1166/C polymorphism with Obstructive Sleep Apnea Hypopn ea Syndrome (OSAHS) and OSAHS accompanied by hypertension(OSAHAHT).And discuss the relativity between the polymorphism and the serious of the Obstructive Sleep Apnea Hypopnea Syndrome(OSAHS) and Obstructive Sleep Apnea Hypopnea Syndrome Accompanied by hypertension (OSAHAHT).The aim is discussing the characteristics between Obstructive Sleep Apnea Syndrome (OSAS) and OSAS a ccompanied by hypertension(OSAHAHT)’s genotype and inves tigate this genotype’s operation in the pathogeny and the develo pment of OSAHS and OSAHAHT.Methods: Sixty-five patients (Male 38,Female 27)were selected randomly in the study. All the OSAHS patients were with no cturnal snoring, apnea and excessive daytime sleepiness syndro me. All subjects were sure to be OSAHS by undergoing overnight polysomnography(PSG).All diagnoses were set according to the Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS)’s guide made by China Medical Academy.That is apn ea hypopnea index AHI≥5/h, The AHI was defined as the ave rage of apneic and hypopneic events per sleep hour. Apnea was defined as an absence of airflow for≥10s, and hypopnea was defined as a reduction of airflow associated with a reduction of oxygen saturation by 4% from baseline. The PCR - RFLR was used to test the A1166/C polymorphism of AT1R genes of 65 OSAHS patients with monitoring their multi - lead sleep map, and 70 health people were selected as control. Forty males with OSAHS were included randomly in the study and twenty age-matched and body mass index(BMI)-matched healthy men served as control subjects. OSAHS patients with nocturnal snoring, apnea and excessive daytime sleepiness syndrome and control subjetcs without those syndromes underwent overnight polysomnography(PSG)and portal sleep apnea monitoring, respectively. Inclusion criteria for the present study were apnea-hypopnea index(AHI)≥5/h for OSAHS patients and AHI<5/h for control subjects. Apnea was defined as an absence of airflow for≥10s, and hypopnea was defined as a reduction of airflow associated with a reduction of oxygen saturation by 4% from baseline. The AHI was defined as the average of apneic and hypopneic events per sleep hour. All patients with OSAHS were divided into two subgroups:31 OSAHS patients without complications(age=47.50±10.30, BMI=28.68±3.16kg/m2)and 34 OSAHAHTpatients(age=52.55±12.74,BMI=29.48±3.89kg/m2). All diagnosis according to the <The China Guideline Of Hypertention prevention> Occurrence of hypertension was later than that of OSAHS in patients with OSAHAHT .Other secondary hypertension (such as renovas cular and endocrinic hypertension)were excluded in OSAHAHT patients. 70 health people(Male 40,Female 30) were selected as control group,(age= 47.65±8.07,BMI=27.13±2.14 kg/m2,)There were no significant differences in age and BMI among control subjects and OSAHS and OSAHAHT subjects, OSAHS were excluded in health group by Stardust. Smoking, drinking, diets, drugs and other disturbance factors were excluded in this study. Fasting venous blood were obtained from all observed subjects after sleep-breathing monitoring within the following 5 minutes in the next morning. After that,extract DNA from the blood by using hydroxybenzene-chloroform ,then duplicate the target DNA segment by using polymerase chain reaction,and then test the polymorphism of AT1 genes A1166/C by restriction endonuclease and electrophorety. Chi-square test was used to statistic the distribution of the AA,AC and CC.Group t-test was used to the data of PSG on OSAHS and OSAHSHAT patients.Result: 1.The frequency of AT1R genetype AA, AC, CC were 88.2%,10.3%,1.5% in health people and 72.3%,26.3%,1.4 % in OSAHS patients, The differences were significant (χ2=5.733,P<0.05) .The frequency of allele AandC were 93% and 7%in health people and 85 % and 15 % in OSAHS patients. And also the frequency were significantly different (χ2=4.861,P < 0.05). The frequency of allele A and C were 62% and 38% in OSAHS patients and 80%,20%in OSAHAHT patients. The frequency were significantly different (χ2 = 5 355, P < 0.05).2.In comparing with OSAHS patients and OSAHAHT patients,the frequency of AT1R gengtype AA,AC,CC were 74%、23%、3% in OSAHS patients and 71%、29%、0% in OSAHAHT patients The differ ence were not significantly (χ2=0.105,P>0.05).C omparing with OSAHS patients and OSAHAHT patients,the frequency of all ele-A was much highier than that of C.3. Compared with OSAHS patients, AHI, average arterial oxygen desaturation and average time of apnea were higher in OSAH AHT patients(t=0.7567, 0.54,2.2615 repectively; p<0.0 5),the difference of the lowest SaO2 and time of the arterial oxygen saturation below 90% per apnea/hypopnea (SaO2<90%)were not significant both in OSAHAHT patients and in OSAHS patients (p>0.05).Conclusions: 1.Despite controlling for age, BMI and excluding disturbance factors such as smoking, drinking, diets and drugs, the polymorphism of angiotensinⅡtype 1 receptor gene A1166/C was associated with OSAHS and OSAHAHT.The frequency of gene type AC+CC was much higher than the healthy group.The frequency of allele-1166C were much higher than the health.Comparing with OSAHS patients and OSAHAHT patients,the frequency of AC+CC gene was not significantly different.While the frequency of Allele-1166C was significantly different.It was correlated positively to not only the average time of apnea but also AHI and the percent of SaO2<90% in one night sleep and was not correlated with the lowest SaO2 both in apnea and in Av.desat.Our study showed the frequency of AC+CC genetype and the allele 1166C gene were much higher in patients with OSAHS and OSAHAHT than those in control subjects as well.There were not difference between the frequency of allele gene and genetype in the patients with OSAHS compared with the patients with OSAHAHT.All these showed the genetype of patients with OSAHS have changed in long-time anoxic sleep.This change was correlated positively to the severity of OSAHS and OSAHAHT.The allele A1166/C gene was not only correlated to Hypertension but also a characteric genetype in patients with OSAHS.Our study documents the close correlation between OSAHS and Hypertension farther.更多还原