外周动脉病在中国高血压人群中的流行病学调查及血管内皮细胞生长因子（VEGF）受体基因多态性与其发病风险的关联研究

【作者】 杨晓敏；

【导师】 惠汝太； 吴海英；

【作者基本信息】 中国协和医科大学 ， 心血管内科， 2007， 博士

【摘要】 目的外周动脉病与冠状动脉粥样硬化性心脏病及脑卒中的发病及死亡密切相关，高血压是外周动脉病的独立危险因素。然而，在中国高血压患者中，外周动脉病的发病率和危险因素还未有报道。方法2004-2005年，我们在中国农村7个社区对年龄40-75岁人口进行了一项横断面调查，共筛查了4，716名高血压患者和833名年龄、性别匹配的非高血压对照。外周动脉病定义为：任何一侧下肢踝臂指数(ABI)≤0.9，高血压定义为：收缩压≥140mmHg，或舒张压≥90mmHg，或既往有明确的高血压病史及服用降压药史。结果在高血压患者中(n=4，716)外周动脉病的患病率为8.7％(n=408)，无高血压的对照组中(n=833)外周动脉病患者占5.0％(42)，低于高血压患者，有统计学差异(P=0.004)。高血压患者中，有外周动脉病者与无外周动脉病者相比，年龄更大，(61±8.6 vs 58±8.6岁，P＜0.01)，传统心血管病危险因素携带更多，包括血压增高(170±22.6 vs 167±22.7 mmHg，P＜0.01)，脉压增大(72±19.7 vs 68±18.9 mmHg，P＜0.01)，血糖增高(5.8±2.2 vs 5.6±1.7 mmol／L，P＜0.05)，总胆固醇增高(5.7±1.3 vs 5.5±1.1 mmol／L，P＜0.05)，血浆尿酸增高(355±98.0 vs 293±86.2 mmol／L，P＜0.05)。多因素logistic回归调整了年龄、性别及其他心血管病危险因素后，与外周动脉病相关的危险因素为：吸烟史(OR=1.65，95％CI 1.18-2.29)，脑卒中病史(OR=1.50，95％CI 1.12-2.00)，血浆尿酸(OR=1.21，95％CI 1.10-1.59)，总胆固醇(OR=1.12，95％CI 1.10-1.59)。结论本研究第一次报道了中国高血压患者外周动脉病患病率，并且发现外周动脉病与传统心血管病危险因素独立相关。目的探讨中国老年人群踝臂指数(ABI)与无症状性颈动脉粥样硬化的关系。方法采用横断面研究方法，2005年8-11月，在参加“青岛港健康研究”的人群中，挑选年龄大于55岁，既往无冠心病，脑卒中，周围动脉病史507人，进行颈动脉超声及四肢血压的检查，同时完善心血管病危险因素的调查。颈动脉粥样硬化定义为：颈动脉内-中膜厚度(IMT)＞1.0mm，或局部斑块形成；ABI＜0.9定义为踝臂指数(ABI)减低。结果颈动脉粥样硬化的患者踝臂指数(ABI)明显减低，ABI＜0.90的比例增加(P＜0.05)；年龄更高，收缩压，脉压增高，BMI增大，血糖增高；既往糖尿病，高血压病史增加(P＜0.05)，进一步调整年龄，性别，血脂，血糖，收缩压，脉压，体重指数后，踝臂指数(ABI)减低与颈动脉粥样硬化独立相关(OR=0.10，95％CI 0.02-0.42，P＜0.01)。结论踝臂指数(ABI)与无症状性颈动脉粥样硬化密切相关，是其独立危险因素。目的外周动脉病是一种动脉粥样硬化性血管损伤性疾病，血管壁病变是其发病基础。血管内皮生长因子受体基因(VEGFR)特异地作用于血管内皮细胞，诱导内皮细胞的增生和迁移、细胞外基质的重建以及毛细血管腔的形成，并增加血管通透性，在血管发育、重构及成熟过程中起着重要的调控作用。方法采用病例对照的研究方法，研究对象年龄在40～75岁，均为汉族，彼此无亲缘关系，分为外周动脉病组(439人)和对照组(1，517人)。根据既往病史及踝臂指数(ABI)≤0.9诊断为外周动脉病，对照组为0.9＜ABI≤1.3的“健康人”，无外周动脉病及其他类型动脉粥样硬化性疾病，性别、年龄与病例组匹配。利用PCR和限制性酶切片断长度多态性(RFLP)的方法对VEGFR-2基因2个SNPs进行基因分型，分析基因多态性与外周动脉病发病风险的关系。结果外周动脉病组rs2071559 C等位基因频率及TC和CC基因型频率显著高于对照组(P＜0.01)，rs1870377 T等位基因频率及AT和TT基因型频率也在病例组中的分布高于对照组(P＜0.01)。多元logistic回归模型校正了传统危险因素的影响后，rs2071559 C等位基因及rs1870377 T等位基因仍然与增加的外周动脉病患病风险相关(OR 1.62，95％CI：1.21～2.17；OR 1.63，95％CI：1.15～2.31)，P＜0.01。结论VEGFR-2基因多态可能是外周动脉病的易感基因。更多还原

【Abstract】 Objectives Peripheral arterial disease (PAD) is associated with morbidity andmortality of coronary heart disease and stroke. Hypertension is an independent riskfactor for peripheral arterial disease. However, the prevalence and risk factors of PADin hypertensive patients has not been studied in China.Methods In order to investigate the prevalence of PAD and its risk factors in China,a cross-sectional study was carried out. Total 4,716 patients with hypertension and833 age-sex matched people without hypertension were recruited; age 40-75, from 7rural communities. PAD was defined as an ankle-brachial index (ABI)≤0.9 in eitherlegs, hypertension was defined as systolic blood pressure≥140mmHg, or diastolicblood pressure≥90mmHg, or history of antihypertensive drug use.Results The prevalence of PAD is 8.7% (n=408) in patients with hypertension(n=4,716), higher than the people without hypertension (5.0%, n=833), P=0.004.Hypertensive patients with PAD were older (61±8.6 vs 58±8.6 years old, P＜0.01), hadmore conventional cardiovascular risk factors including higher systolic blood pressure(170±22.6 vs 167±22.7 mmHg, P＜0.01), pulse pressure (72±19.7 vs 68±18.9 mmHg,P＜0.01), higher blood glucose (5.8±2.2 vs 5.6±1.7mmol/L, P＜0.05), total cholesterol(5.7±1.3 vs 5.5±1.1 mmol/L, P＜0.05), and serum uric acid (355±98.0 vs 293±86.2mmol/L, P＜0.05) than the hypertensive patients without PAD. After adjusted for sex,age and other cardiovascular risk factors by using multiple logistical regressionanalysis, PAD remained associated with current smoking (OR=1.65, 95% CI1.18-2.29), history of stroke (OR=1.50, 95% CI, 1.12-2.00), serum uric acid(OR=1.21, 95% CI, 1.10-1.59), total cholesterol (OR=1.12, 95% CI, 1.10-1.59).Conclusion This study provides the prevalence of PAD in Chinese patients with hypertension for the first time; and PAD is independently associated withconventional cardiovascular risk factors. Objective The purpose of this study was to detect the relationship betweenankle-brachial index (ABI) and preclinical carotid atherosclerosis in elderly Chinese.Methods In order to investigate the association between ABI and preclinical carotidatherosclerosis in elderly Chinese, a cross-sectional study was carried out. Total 507patients older than 55 years from the health study of QingDao harbor were recruited.None of them had history of clinical coronary artery disease, stroke and peripheralartery disease. Blood pressure and ultrasound examination were performed. Carotidatherosclerosis was defined as carotid intima-media thickness (IMT)＞1.0mm orcarotid plaque. Low ankle-brachial index (ABI) was defined as ABI＜0.9 in eitherlegs.Results The higher percentage of ankle-brachial index (ABI)＜0.9 and history ofdiabetic mellitus, hypertension were investigated in subjects with carotidatherosclerosis than those without carotid atherosclerosis, (p＜0.05). Subjects withcarotid atherosclerosis were older, had more conventional cardiovascular risk factorsincluding higher systolic blood pressure, pulse pressure, higher blood glucose, bodymass index (BMI) than those without carotid atherosclerosis, (p＜0.05). Afteradjusted for sex, age and other cardiovascular risk factors by using multiple logisticalregression analysis, ABI was negatively associated with carotid atherosclerosis(OR=0.10, 95%CI 0.02-0.42, P＜0.01).Conclusion Low ABI is a strong predictor for preclinical carotid atherosclerosis inelderly Chinese Objective Peripheral arterial disease (PAD) is a kind of atherosclerotic diseaseresulted from vascular damage. The lesion in vascular wall is the underlyingpathological mechanism. Vascular endothelial growth factor (VEGF), which is apotent endothelial cell mitogen and vascular permeability-enhancing factor, plays avital role in the process of vascular development and maturation via its tyrosinekinase receptors.Methods A case-control study was carried out. Total 439 patients with peripheralarterial disease and 1,517 age-sex matched individuals without atheroscleroticdiseases such as stroke, coronary arterial disease and PAD were recruited. They allclaimed as Han nationality, with age 40-75 years old, without relative between eachother. PAD was defined as an ankle-brachial index (ABI)≤0.9 in either legs. In orderto determine the relationship between the polymorphisms of the VEGF-2 gene and therisk of PAD, two polymorphisms of the VEGF-2 gene were genotyped by PCR andrestriction enzyme analysis.Results -604C allele frequency and genotype frequencies of TC and CC in thepatients group were much higher than which in the control group (P＜0.01), +1719Tallele frequency and genotype frequencies of AT and TT were also higher in thepatients group than that in the control group (P＜0.01). After adjustment fortraditional cardiovascular risk factors by using multiple logistical regression analysis,allele frequencies of-604C and +1719T were associated with PAD significantly (OR1.62, 95%CI: 1.21～2.17; OR 1.63, 95%CI: 1.15～2.31, P＜0.01). Conclusion the polymorphisms of the VEGF-2 gene is associated with the risksusceptibility to peripheral arterial disease更多还原