AT1R的基因多态性与OSAHS及OSAHS合并高血压的相关性
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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。
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 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.
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。
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
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.
引文
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8 Peter P, Yingal M, Adriaan A, et al. Angiotensin Ⅱ typel receptor A1166C Gene polymorphism is associated with Increased Response to Angiotensin Ⅱi n human Arteries [J]. Hypertension,2000,35(3):717-729
9 Arter JL,Chi DS,Girish M et al.Obstructive sleep apnea,in fla mmation, and cardiopulmonary disease.Front Biosci.200 4,9: 2892-2900
10 Maekawa M, Shiomi T, Usui K et al.Prevalence of ischemic heart disease among patients with sleep apnea syndrome.Ps ychiatry Clin Neurosci 1998,52(2):219-220
11 Silverberg DS,Oksenberg A.Are sleep-related breathing disorders important contributing factors to the production of essential hypertension?Curr Hypertens Rep,2001,3: 209-215
12 Peppard PE,Young T,Palta M,et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med,2000,324(19):1378-1384
13 Kimoff RJ,Brooks D,Horner RL,et al. Ventilatory and arousal responses to hypoxia and hypercapnia in a canine model of obstructive sleep apnea. Am J Rspir Crit Care Med, 1997,156(3 pt 1):886-894
14 Stradling JR,Partlett J,Davies RJ,et al. Effect of short term graded withdrawal of nasal continous positive airway p ressure on systemic blood pressure in patients with obstructi ve sleep apnoea. Blood press,1996,5(4):234-240
15 Elmasry A , Lindberg E , Hedner J , et al . Obst ructive sleep apnoea and urine catecholamines in hypertensive males : ap opulation2based study Eur Respir J ,2002 ,19 (3) :511-517
16 Nachtmann A , Stang A , Wang YM , et al . Association of obstructive sleep apnea and stenotic artery disease in is che micst roke patient s. At herosclerosis ,2003 ,16(2):301-307
17 李少英,樊 红,罗家滨等.血管紧张素的型受体基因多态位点 1166 在中国正常中的分布[J].中国优生与遗传杂志1997,5:15
18 蔡晓敏,江时森.科技进步与心血管病学 50 年展望[J].医学研究生学报,2001,14(4):356-359
19 江时森著.经典心脏病学[M].南京:南京出版社,1992.5
20 KatsuyaT,HigakiJ,OgiharaT.Geneloci and polymorphis ms of angiotensin Ⅱ receptor. [J] Nippon Rinsho 1999,57 1020-1027
21 Vgontzas AN,Bixler EO,Chrousos GP1 Sleep apnea is a ma nifestation of the metabol syndrome [J] 1 sleep Med Rev, 2005;9 211-224
22 almer LJ , Buxbaum SG, Larkin EK, et al . Whole ge nome scan for obstructive sleep apnea and obesity in African - American families. [J]Am JRespir Crit Care Med , 2004 ,169 :1314-1321
23 Palmer L, Redline S. Genomic approaches to understa nding obstructive sleep apnea. [J] Respir Physio lNeur obiol,2003, 135 :187-205
24 Jennum P , Hein P , Suadicani H , et al . Snoring , family history and genetic markers in men : the Copenhagen male st udy. [J] Chest , 1995,107:1289-1293
25 Li DY,Zhang YC,Philips MI,et al,Up regulation of endothelial Receptor for oxidized, lowdensity lipoprotein (LOX-1)in cultured human coronary artery endo thelial cells by angiotensin II type1 receptor activation1 Circ Res,199 9,84: 1043-1049
26 Nickening G,Bohm M. Regulation of the angiotensin AT-1 receptor expression by hypereholesterolemia[J] Eur J Res 1997;2:285-289
27 Katsumata K, Okada T, MiynoM, et al. High iucidence of sleep apnea syndrome in a male diabetic population [ J ]. Diabete s Res Clin Pract, 1991, 13 (1) : 45-47
28 周燕斌,谢灿茂,肖海鹏,等. 阻塞性睡眠呼吸暂停综合征对血脂及糖代谢的影响[ J ]. 新医学, 2001,32 (9) : 530-531, 534
29 Marrone O, Riccobono L. Catecholamines and blood pressure in obstructive sleep apnea syndrome [ J ].Ch est,1993,103(3) : 722-727
30 Stradling JR. Relation between systemic hypertension and sleep hypo xemia or snoring:analysis in 748 men drawn from general practice. [J] BrMed J,1990,300:75-7 8
31 Castellano M, Muiesan M L,Beschi Metal AngiotensiⅡtype1 receptor AC1166 polymorphism Relationship with blood pressure and cardiovascular structure. Hypertension, 1996,28 (6):1076-1080
32 VanGeelPP, PintoYM, VoorsAA, BuikemaH, OostergaM, Crijns HJ, etal.Angiotensin Ⅱtype1 receptor A1166/C gene polymorphismis associated with an increased response to angiotensin Ⅱ in human arteries. [J] Hypertension, 2000,35:717-721
1 Bonnardeaux A, Davies E, Jeunemaitrex, et al. Angiotensin Ⅱtypel receptor gene polymorphisms in humanes sential hypertension [J]. Hypertension, 1994, 24 (1): 63-69
2 《阻塞性睡眠呼吸暂停低通气综合征诊治指南 (草案)》中华内科杂志 2003, Vol 42 No,8
3 肖毅,黄席珍,邱长春,等血管紧张素转换酶基因多态性与阻塞性睡眠呼吸暂停低通气综合征.中华结核和呼吸杂志,1998,21:489-491
4 Young T , Palta M, Dempsey J , et al . The occurrence of sleep2 disordered breathing among middle2aged adults. N Engl J Med , 1993 ,328 :1230-1235
5 Redline S , Strohl KP. Recognition and consequences of obstructive sleep apnea2hypopnea syndrome. Clin Chest Med , 1998 , 19 : 1219
6 Ancoli2Israel S , Kripke DF , Klauber MR , et al . Sleep2 disordered breathing in community2dwelling elderly. Sleep ,1991 ,14 : 486-495
7 Duran J , Esnaola S , Rubio R , et al . Obstructive sleep apnea hypopnea and related clinical features in a population2based sample of subjects aged 30 to 70 yr. AmJ Respir Crit Care Med , 2001 , 163(3 Pt 1) :685-689
8 Bixler EO , Vgontzas AN , Lin HM, et al . Prevalence of sleep2 disordered breathing in women : effects of gender. Am J Respir Crit Care Med ,2001 , 163 (3 Pt 1) :608-613
9 Ip MS , LamB , Lauder IJ , et al . A community study of sleep2 disordered Breathing in middle2aged Chinese men in Hong Kong. Chest , 2001 ,119 :62-69
10 Urushihara N,et al. Eur J Pediatr Surg,1999; 9:430~432
11 Fletcher EC,et al. Crit Care Med, 1991, 19: 1158-1164
12 Sanner BM,et al. Arch Int Med,1997;157:2483-2486
13 Peppard PE,et al,N Engl J Med,2000;342:1378-1384
14 James M,et al.Chest,1990,97:1220-1224
15 Engleman HM, et al. Sleep, 2000;23(suppl):4s102-108
16 Grunstein RR,et al. J Clin Endocrinol Metab 1989; 68: 352 -35
17 HeinemannS,etal.Pneumologie,1995,49(suppl):1139-1141
18 Goldstein SJ, et al.Acta Endocrinol,1987;116:95-102
19 Yaggi H,Mohsenin V. Obstructive sleep apnoea and stroke[J]. Lancet Neurol,2004,3(6):333- 342
20 Aikens JE, Caruana-Montaldo B, Vanable PA, et al. MMPI correlates of sleep and respiratory disturbance in obstructive sleep apnea [J].Sleep,1999, 22:362- 369
21 Punjabi NM,Shahar E,Redline S,et al.Sleep disordered breathing,glucose intolerance,and insulin resistance:the sleep heart health study[J].Am J Epidemiol, 2004,160:521- 530
22 刘英梅,伍卫.血管紧张素Ⅱ受体阻断剂在心血管疾病中的应用与展望[J].国外医学·内科学分册,1998, 25(6):231
23 王静,尖子刚,刘兆昶.血管紧张素拮抗剂在心血管疾病的临床应用[J]. 华厦医学,2001,9(6):981
24 Kang PM,Landau AJ,Eberhardt RT,et al.Am Heart J,1994,127(5):1388-1401
25 Timmernans PBMWM, Smith RD. Eur Heart: J 1994, 15(suppl D):79-87
26 WangWY,etal.ClincGenet,1997;51(1):31
27 CastellanoM,etal.Hypertension,1997;28(6):1076
28 BenetosA,TopouchianJ,Ricard S, et al. Influence of an giotensinⅡ typel receptor gene polymorphism on arotic stiff ness in nerver treated hypertensive patients [J]. Hypertensio n,1995,26(1):4447
29 Peter P, Yingal M, Adriaan A, et al. Angiotensin Ⅱ typel receptor A1166C Gene polymorphism is associated with Increased Response to AngiotensinⅡ in human Arteries [J].Hypertension,2000, 35(3):717729
30 上海市医学会呼吸病学分会睡眠呼吸疾病学组.上海市30 岁以上人群阻塞性睡眠呼吸暂停低通气综合征流行病学调查[J].中华结核和呼吸杂志,2000,26(5):268- 272
31 Nieto FJ, Young TB,Lind BK, et al. Association of sle ep2disorder2ed breathing, sleep apnea, and hypertension in a la rge community2based study. Sleep Heart Health Study [ J ]. JA MA, 2000, 283:1829 – 1836
32 Peppard PE, Young T, PaltaM, et al. Prospective stud y of the asso2ciation between sleep2disordered breathing and hy pertension[ J ]. Nengl J Med, 2000, 342: 1378 – 1384
33 Lologan AG, Perilikowski SM,Mente A, et al. High p revalence ofunrecognized sleep apnea in drug resistanthyperten sion[ J ]. J Hypertens, 2001, 19: 2271 – 2277
34 Seventh Report of the JointNational Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure[ J ]. Hypertension, 2003, 42: 1206 – 1252
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64 Leuenberger U, Jacob E,Sweer L,et al.Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia[J].J Appl Physiol,1995,79(2):581-588
65 Kraiczi H, Hedner J, Peker Y, et al. Comparison of aten olo, amlodipine,enalapril,hydrochlorothiazide,and losatan for antihypertensive treatment in patients with obstructive sleep apnea[J].AmJ Respir Crit Care Med, 2000,161:1423 -1428
66 Field LJ,Veress AT,Steinhelper ME,et al.Kidney functi on in ANF-transgenic mice:effect of blood volume expansion [J].Am J Physiol,1991,260(1pt2):R1-5
67 Kato M, Roberts-Thomson P, Phillips BG,et al.Impair ment of endothelium-dependent vasodiation of resistance ves sels in patients with obstructive sleep apnea[J],Criculation, 2 000,102:2607-2610
2 刘力生.2004 年中国高血压防治指南(实用本).中华心血管病杂志,2004,32(12):1060-1064
3 Coccagna G,Mantovani M,Brignani F,et al. Continuous recording of the pulmonary and systemic arterial pressure during sleep in syndromes of hypersomnia with periodic breathing. Bull Physiopa- thol Respir (Nancy), 1972,8(5):1159-1172
4 Carlson J,Davies R,et al. Obstructive sleep apnea and blo od pressure elevation: what is the relationship? Working G roup on OSA and Hypertension. Blood Press. 1993,2(3): 16 6-182
5 Bonnardeaux A,Davies E,Jeunemaitrex,et al.Angiotensin Ⅱtype1 receptor gene polymorphisms in humanes sential hypertension .Hypertension,1994,24 63-69
6 WangWY,etal.ClincGenet,1997;51(1):31
7 BenetosA,TopouchianJ,Ricard S,et al. Influence of angiot ensin Ⅱ typel receptor gene polymorphism on arotic stiff ness in nerver treated hypertensive patients [J]. Hypertensi on,19 95,26(1):4447
8 Peter P, Yingal M, Adriaan A, et al. Angiotensin Ⅱ typel receptor A1166C Gene polymorphism is associated with Increased Response to Angiotensin Ⅱi n human Arteries [J]. Hypertension,2000,35(3):717-729
9 Arter JL,Chi DS,Girish M et al.Obstructive sleep apnea,in fla mmation, and cardiopulmonary disease.Front Biosci.200 4,9: 2892-2900
10 Maekawa M, Shiomi T, Usui K et al.Prevalence of ischemic heart disease among patients with sleep apnea syndrome.Ps ychiatry Clin Neurosci 1998,52(2):219-220
11 Silverberg DS,Oksenberg A.Are sleep-related breathing disorders important contributing factors to the production of essential hypertension?Curr Hypertens Rep,2001,3: 209-215
12 Peppard PE,Young T,Palta M,et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med,2000,324(19):1378-1384
13 Kimoff RJ,Brooks D,Horner RL,et al. Ventilatory and arousal responses to hypoxia and hypercapnia in a canine model of obstructive sleep apnea. Am J Rspir Crit Care Med, 1997,156(3 pt 1):886-894
14 Stradling JR,Partlett J,Davies RJ,et al. Effect of short term graded withdrawal of nasal continous positive airway p ressure on systemic blood pressure in patients with obstructi ve sleep apnoea. Blood press,1996,5(4):234-240
15 Elmasry A , Lindberg E , Hedner J , et al . Obst ructive sleep apnoea and urine catecholamines in hypertensive males : ap opulation2based study Eur Respir J ,2002 ,19 (3) :511-517
16 Nachtmann A , Stang A , Wang YM , et al . Association of obstructive sleep apnea and stenotic artery disease in is che micst roke patient s. At herosclerosis ,2003 ,16(2):301-307
17 李少英,樊 红,罗家滨等.血管紧张素的型受体基因多态位点 1166 在中国正常中的分布[J].中国优生与遗传杂志1997,5:15
18 蔡晓敏,江时森.科技进步与心血管病学 50 年展望[J].医学研究生学报,2001,14(4):356-359
19 江时森著.经典心脏病学[M].南京:南京出版社,1992.5
20 KatsuyaT,HigakiJ,OgiharaT.Geneloci and polymorphis ms of angiotensin Ⅱ receptor. [J] Nippon Rinsho 1999,57 1020-1027
21 Vgontzas AN,Bixler EO,Chrousos GP1 Sleep apnea is a ma nifestation of the metabol syndrome [J] 1 sleep Med Rev, 2005;9 211-224
22 almer LJ , Buxbaum SG, Larkin EK, et al . Whole ge nome scan for obstructive sleep apnea and obesity in African - American families. [J]Am JRespir Crit Care Med , 2004 ,169 :1314-1321
23 Palmer L, Redline S. Genomic approaches to understa nding obstructive sleep apnea. [J] Respir Physio lNeur obiol,2003, 135 :187-205
24 Jennum P , Hein P , Suadicani H , et al . Snoring , family history and genetic markers in men : the Copenhagen male st udy. [J] Chest , 1995,107:1289-1293
25 Li DY,Zhang YC,Philips MI,et al,Up regulation of endothelial Receptor for oxidized, lowdensity lipoprotein (LOX-1)in cultured human coronary artery endo thelial cells by angiotensin II type1 receptor activation1 Circ Res,199 9,84: 1043-1049
26 Nickening G,Bohm M. Regulation of the angiotensin AT-1 receptor expression by hypereholesterolemia[J] Eur J Res 1997;2:285-289
27 Katsumata K, Okada T, MiynoM, et al. High iucidence of sleep apnea syndrome in a male diabetic population [ J ]. Diabete s Res Clin Pract, 1991, 13 (1) : 45-47
28 周燕斌,谢灿茂,肖海鹏,等. 阻塞性睡眠呼吸暂停综合征对血脂及糖代谢的影响[ J ]. 新医学, 2001,32 (9) : 530-531, 534
29 Marrone O, Riccobono L. Catecholamines and blood pressure in obstructive sleep apnea syndrome [ J ].Ch est,1993,103(3) : 722-727
30 Stradling JR. Relation between systemic hypertension and sleep hypo xemia or snoring:analysis in 748 men drawn from general practice. [J] BrMed J,1990,300:75-7 8
31 Castellano M, Muiesan M L,Beschi Metal AngiotensiⅡtype1 receptor AC1166 polymorphism Relationship with blood pressure and cardiovascular structure. Hypertension, 1996,28 (6):1076-1080
32 VanGeelPP, PintoYM, VoorsAA, BuikemaH, OostergaM, Crijns HJ, etal.Angiotensin Ⅱtype1 receptor A1166/C gene polymorphismis associated with an increased response to angiotensin Ⅱ in human arteries. [J] Hypertension, 2000,35:717-721
1 Bonnardeaux A, Davies E, Jeunemaitrex, et al. Angiotensin Ⅱtypel receptor gene polymorphisms in humanes sential hypertension [J]. Hypertension, 1994, 24 (1): 63-69
2 《阻塞性睡眠呼吸暂停低通气综合征诊治指南 (草案)》中华内科杂志 2003, Vol 42 No,8
3 肖毅,黄席珍,邱长春,等血管紧张素转换酶基因多态性与阻塞性睡眠呼吸暂停低通气综合征.中华结核和呼吸杂志,1998,21:489-491
4 Young T , Palta M, Dempsey J , et al . The occurrence of sleep2 disordered breathing among middle2aged adults. N Engl J Med , 1993 ,328 :1230-1235
5 Redline S , Strohl KP. Recognition and consequences of obstructive sleep apnea2hypopnea syndrome. Clin Chest Med , 1998 , 19 : 1219
6 Ancoli2Israel S , Kripke DF , Klauber MR , et al . Sleep2 disordered breathing in community2dwelling elderly. Sleep ,1991 ,14 : 486-495
7 Duran J , Esnaola S , Rubio R , et al . Obstructive sleep apnea hypopnea and related clinical features in a population2based sample of subjects aged 30 to 70 yr. AmJ Respir Crit Care Med , 2001 , 163(3 Pt 1) :685-689
8 Bixler EO , Vgontzas AN , Lin HM, et al . Prevalence of sleep2 disordered breathing in women : effects of gender. Am J Respir Crit Care Med ,2001 , 163 (3 Pt 1) :608-613
9 Ip MS , LamB , Lauder IJ , et al . A community study of sleep2 disordered Breathing in middle2aged Chinese men in Hong Kong. Chest , 2001 ,119 :62-69
10 Urushihara N,et al. Eur J Pediatr Surg,1999; 9:430~432
11 Fletcher EC,et al. Crit Care Med, 1991, 19: 1158-1164
12 Sanner BM,et al. Arch Int Med,1997;157:2483-2486
13 Peppard PE,et al,N Engl J Med,2000;342:1378-1384
14 James M,et al.Chest,1990,97:1220-1224
15 Engleman HM, et al. Sleep, 2000;23(suppl):4s102-108
16 Grunstein RR,et al. J Clin Endocrinol Metab 1989; 68: 352 -35
17 HeinemannS,etal.Pneumologie,1995,49(suppl):1139-1141
18 Goldstein SJ, et al.Acta Endocrinol,1987;116:95-102
19 Yaggi H,Mohsenin V. Obstructive sleep apnoea and stroke[J]. Lancet Neurol,2004,3(6):333- 342
20 Aikens JE, Caruana-Montaldo B, Vanable PA, et al. MMPI correlates of sleep and respiratory disturbance in obstructive sleep apnea [J].Sleep,1999, 22:362- 369
21 Punjabi NM,Shahar E,Redline S,et al.Sleep disordered breathing,glucose intolerance,and insulin resistance:the sleep heart health study[J].Am J Epidemiol, 2004,160:521- 530
22 刘英梅,伍卫.血管紧张素Ⅱ受体阻断剂在心血管疾病中的应用与展望[J].国外医学·内科学分册,1998, 25(6):231
23 王静,尖子刚,刘兆昶.血管紧张素拮抗剂在心血管疾病的临床应用[J]. 华厦医学,2001,9(6):981
24 Kang PM,Landau AJ,Eberhardt RT,et al.Am Heart J,1994,127(5):1388-1401
25 Timmernans PBMWM, Smith RD. Eur Heart: J 1994, 15(suppl D):79-87
26 WangWY,etal.ClincGenet,1997;51(1):31
27 CastellanoM,etal.Hypertension,1997;28(6):1076
28 BenetosA,TopouchianJ,Ricard S, et al. Influence of an giotensinⅡ typel receptor gene polymorphism on arotic stiff ness in nerver treated hypertensive patients [J]. Hypertensio n,1995,26(1):4447
29 Peter P, Yingal M, Adriaan A, et al. Angiotensin Ⅱ typel receptor A1166C Gene polymorphism is associated with Increased Response to AngiotensinⅡ in human Arteries [J].Hypertension,2000, 35(3):717729
30 上海市医学会呼吸病学分会睡眠呼吸疾病学组.上海市30 岁以上人群阻塞性睡眠呼吸暂停低通气综合征流行病学调查[J].中华结核和呼吸杂志,2000,26(5):268- 272
31 Nieto FJ, Young TB,Lind BK, et al. Association of sle ep2disorder2ed breathing, sleep apnea, and hypertension in a la rge community2based study. Sleep Heart Health Study [ J ]. JA MA, 2000, 283:1829 – 1836
32 Peppard PE, Young T, PaltaM, et al. Prospective stud y of the asso2ciation between sleep2disordered breathing and hy pertension[ J ]. Nengl J Med, 2000, 342: 1378 – 1384
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