中国原发性高血压伴高同型半胱氨酸血症遗传环境危险因素分析
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摘要
目的：高血压和高同型半胱氨酸血症(HHcy)是我国居民脑卒中发生的最重要的两个可控危险因素,本研究拟采用大样本社区调查了解中国农村高血压患者血清同型半胱氨酸(Hcy)水平以及HHcy人群患病率,并探索可能影响HHcy的主要影响因素。
方法：2008.5-2009.8在安徽省安庆市和江苏省连云港市的两个农村社区原发性高血压患者,进行血压测量、问卷调查、临床检查和血清Hcy浓度及亚甲基四氢叶酸还原酶(MTHFR)基因多态性检测。HHcy的诊断标准为血tHcy≧10umol/L.通过单因素和多因素相关分析筛选可能导致HHcy的重要遗传和环境因素
结果：本研究共包括原发性高血压患者21373例,平均年龄60.0±7.5岁,其中男性8610例(40.3%),女性12763(59.7%)。男性Hcy几何分布为13.1±8.0umol/L,女性为10.2±4.3umol/L;HHcy的发病率男性为65.3%,女性为44.0%。在调整了年龄、性别、生活方式、基因型、血压、地域、BMI等因素后,连云港和安庆地区HHcy比例在男性无明显区别,而连云港地区女性高Hcy比例显著低于安庆地区(OR=0.86;95%CI:0.78-0.94, P=0.002)年龄在两个性别中都和HHcy发病率呈线性增加趋势。高血压严重程度在女性中对于HHcy患病率有显著性影响(中度OR=0.86；95%CI：0.79-0.94；重度OR=0.89,95%C10.79-0.94),在男性中却没有显著关系。抽烟和HHcy患病率在两个性别中均没有显著关系,而饮酒和HHcy患病率均呈显著负相关关系。BMI和HHcy患病率在男性和女性中都呈现显著正相关关系。MTHFR677C/T多态性和HHcy在男性和女性中都保持高度相关。TT基因型HHcy发病率显著高于其他基因型, CC型相比,男性中CT型和TT型的OR值分别为1.32(95%CI：1.19-1.47)和3.92(95%CI：3.39-4.52),在女性CT型和TT型的OR值分别为1.23(95%CI：1.12-1.35)和3.42(95%CI：3.07-3.70)。
结论：中国农村社区高血压患者中HHcy发病率高,性别,年龄,和MTHFR677C/T多态性是影响HHcy患病率的重要因素。
目的：高血压和高同型半胱氨酸血症(Hyperhomocysteinemia,HHcy)是我国脑卒中高发的最重要危险因素,亚甲基四氢叶酸还原酶(MTHFR)677C/T多态性与HHcy关系已经在多个人群中证实,本研究在不同高血压人群中系统分析了MTHFR与HHcy的关系,并且评价其关联关系以及预测HHcy模型的敏感性和特异性。
方法：研究样本分别来自四项独立的遗传流行病学研究：1)依那普利叶酸流行病学研究(242人)；2)氨氯地平特拉唑嗪药物基因组课题(238人)；3)依那普利叶酸片多中心、随机、双盲三模拟、平行对照II期临床研究课题(464人)；以及4)苯那普利药物基因组研究(114),共计1058人。所有进入四个的研究对象均采用HPLC方法测定血浆Hcy水平,TaqMan系统检测MTHFR677C/T基因型。
结果：(1)研究发现：男性HHcy水平均高于女性,MTHFR TT基因型患者均显著高于其它基因型,增高范围在38%到68%之间,平均增高51%,TT基因型可以解释14%的HHcy的变异；(2)把HHcy水平分别定义为轻度(≥10μmol/L),中度(≥15μmol/L))和重度(≥20μmo1/L))作为结果变量与677C/T基因型进行Logistic回归分析,与CC基因型相比,TT基因型其相应的OR值分别为3.9(95%CI：2.4-6.4),6.5(95%CI：4.0-10.6),和17.9(95%CI：8.4-38.1)；(3)MTHFR677C/T多态性预测HHcy的效能随着HHcy的Cut-off值的升高而增加,敏感性从31%增加到71%,特异性为85%下降到80%,在回归模型中增加了性别年龄因素后,预测模型的敏感度显著提高。
结论：原发性高血压人群中亚甲基四氢叶酸还原酶(MTHFR) TT基因型的HHcy生率高于其它基因型；TT基因型预测HHcy具有良好的敏感性和特异性,因此结合高血压诊断,可以用于筛查和辨认脑卒中高发人群,进行早期预防。
Background:Hyperhomocysteinemia (HHcy) is a well established and independent risk factor for stroke and cardiovascular disease (CVD). Furthermore, an increased homocysteine (Hcy) level showed a more than multiplicative effect on risk in hypertensive subjects (H-type hypertension) with a relative risk of10-folds for stroke..
Objective:To obtain the prevalence of HHcy in rural Chinese hypertensive subjects and to identify the major determiants of HHcy..
Methods:We conducted a community-based cross-sectional study in two rural regions of Northern (Lianyungang) and Southern (Anqing) China from2008to2009. The Hcy levels were measured by enzyme immunoassay methods and the methylenetetrahydrofolate reductase (MTHFR)677C/T polymorphism was determined by high-throughput TaqMan allelic discrimination assay. Blood pressure (BP), body mass index (BMI) and other related demographic and lifestyle information were obtained through a standard questionnaire. Multivariate logistic regression model was performed to evaluate the associations of HHcy with the potential risk factors.
Results:A total of21,373hypertensive patients with the age range of45to75were available for the data analysis. Overall, the prevalence of HHcy (defined as Hcy≥10.0umol/L) was65.3%in males and43.0%in women in Chinese rural hypertensive patients. Gender, age, alcohol consumption, and MTHFR677C/T were associated with HHcy risk. On the logistic regression analysis, multivariate modeling further identified that among men, the odds ratios of HHcy were significantly increased from1.28to3.01with age groups from50-55to70-75yrs of age, compared with the youngest reference group (45-50yrs of age). Similarly the graded increase in odds ratios of HHcy from1.45to5.74were observed with increased age groups among women. Women in Anqing had a significantly increased prevalence of HHcy than in Lianyungang (OR=0.85;95%CI:0.68-1.07),but not men. The subjects with CT and TT genotype had significantly higher risks of HHcy both in men1.32(95%CI:1.19-1.47) and3.92(95%CI:3.39-4.52) Alcohol consumption is significantly associated was20%reduction in risk of HHcy compared with non-drinkers. Cigarette smoking is not significantly associated with HHcy in this population.
Conclusions:our study found that there was a high prevalence of HHcy in rural Chinese hypertensive patients and that the gender, age, and MTHFR677C/T were the major determinants of HHcy.
Objective:To evaluate the association of methylenetetrahydrofolate reductase (MTHFR) gene677C/T polymorphism with hyperhomocysteinemia (HHcy) in Chinese hypertensive patients.
Methods:We measured plasma tHcy level and677C/T genotype in1058Chinese hypertensive patients from four previous studies. We used10,15,20μmol/L as cut-off values for the definition of mild, modest, and severe HHcy, respectively, to evaluate the association of HHcy with MTHFR677C/T polymorphism and calculate the sensitivity and specificity. Logistic modelswere use to estimate the odds ratios of HHcy with MTHFR677C/T genotypes adjusting for potential confounders. The receiver operating characteristics of the models were evaluated with and without inclusion of age and gender.
Results:MTHFR677TT genotype is significantly and consistently associated with a higher Homocysteine across the four studies, with an increase in size ranging from38%to68%in the four studies and51%overall. The677C/T polymorphism independently explained about14%of the total variance of the normalized Hcy. The adjusted Odds Ratios for the TT genotype were3.9(95%CI:2.4-6.4),6.5(95%CI:4.0-10.6), and17.9(95%CI:8.4-38.1) for mild, modest, and severe HHcy, respectively. The predicting performance increased with HHcy severity, with sensitivity improved from31.0%for mild HHcy to70.3%for severe HHcy, and with specificity slightly decreased from85.4%to80.3%. Inclusion of gender and age as predictors significantly improves the sensitivity, especially for predicting mild HHcy.
Conclusion:With an excellent specificity and moderate sensitivity, the MTHFR677C/T polymorphism could be a useful screening marker for severe HHcy in hypertensive patients.
方法：2008.5-2009.8在安徽省安庆市和江苏省连云港市的两个农村社区原发性高血压患者,进行血压测量、问卷调查、临床检查和血清Hcy浓度及亚甲基四氢叶酸还原酶(MTHFR)基因多态性检测。HHcy的诊断标准为血tHcy≧10umol/L.通过单因素和多因素相关分析筛选可能导致HHcy的重要遗传和环境因素
结果：本研究共包括原发性高血压患者21373例,平均年龄60.0±7.5岁,其中男性8610例(40.3%),女性12763(59.7%)。男性Hcy几何分布为13.1±8.0umol/L,女性为10.2±4.3umol/L;HHcy的发病率男性为65.3%,女性为44.0%。在调整了年龄、性别、生活方式、基因型、血压、地域、BMI等因素后,连云港和安庆地区HHcy比例在男性无明显区别,而连云港地区女性高Hcy比例显著低于安庆地区(OR=0.86;95%CI:0.78-0.94, P=0.002)年龄在两个性别中都和HHcy发病率呈线性增加趋势。高血压严重程度在女性中对于HHcy患病率有显著性影响(中度OR=0.86；95%CI：0.79-0.94；重度OR=0.89,95%C10.79-0.94),在男性中却没有显著关系。抽烟和HHcy患病率在两个性别中均没有显著关系,而饮酒和HHcy患病率均呈显著负相关关系。BMI和HHcy患病率在男性和女性中都呈现显著正相关关系。MTHFR677C/T多态性和HHcy在男性和女性中都保持高度相关。TT基因型HHcy发病率显著高于其他基因型, CC型相比,男性中CT型和TT型的OR值分别为1.32(95%CI：1.19-1.47)和3.92(95%CI：3.39-4.52),在女性CT型和TT型的OR值分别为1.23(95%CI：1.12-1.35)和3.42(95%CI：3.07-3.70)。
结论：中国农村社区高血压患者中HHcy发病率高,性别,年龄,和MTHFR677C/T多态性是影响HHcy患病率的重要因素。
目的：高血压和高同型半胱氨酸血症(Hyperhomocysteinemia,HHcy)是我国脑卒中高发的最重要危险因素,亚甲基四氢叶酸还原酶(MTHFR)677C/T多态性与HHcy关系已经在多个人群中证实,本研究在不同高血压人群中系统分析了MTHFR与HHcy的关系,并且评价其关联关系以及预测HHcy模型的敏感性和特异性。
方法：研究样本分别来自四项独立的遗传流行病学研究：1)依那普利叶酸流行病学研究(242人)；2)氨氯地平特拉唑嗪药物基因组课题(238人)；3)依那普利叶酸片多中心、随机、双盲三模拟、平行对照II期临床研究课题(464人)；以及4)苯那普利药物基因组研究(114),共计1058人。所有进入四个的研究对象均采用HPLC方法测定血浆Hcy水平,TaqMan系统检测MTHFR677C/T基因型。
结果：(1)研究发现：男性HHcy水平均高于女性,MTHFR TT基因型患者均显著高于其它基因型,增高范围在38%到68%之间,平均增高51%,TT基因型可以解释14%的HHcy的变异；(2)把HHcy水平分别定义为轻度(≥10μmol/L),中度(≥15μmol/L))和重度(≥20μmo1/L))作为结果变量与677C/T基因型进行Logistic回归分析,与CC基因型相比,TT基因型其相应的OR值分别为3.9(95%CI：2.4-6.4),6.5(95%CI：4.0-10.6),和17.9(95%CI：8.4-38.1)；(3)MTHFR677C/T多态性预测HHcy的效能随着HHcy的Cut-off值的升高而增加,敏感性从31%增加到71%,特异性为85%下降到80%,在回归模型中增加了性别年龄因素后,预测模型的敏感度显著提高。
结论：原发性高血压人群中亚甲基四氢叶酸还原酶(MTHFR) TT基因型的HHcy生率高于其它基因型；TT基因型预测HHcy具有良好的敏感性和特异性,因此结合高血压诊断,可以用于筛查和辨认脑卒中高发人群,进行早期预防。
Background:Hyperhomocysteinemia (HHcy) is a well established and independent risk factor for stroke and cardiovascular disease (CVD). Furthermore, an increased homocysteine (Hcy) level showed a more than multiplicative effect on risk in hypertensive subjects (H-type hypertension) with a relative risk of10-folds for stroke..
Objective:To obtain the prevalence of HHcy in rural Chinese hypertensive subjects and to identify the major determiants of HHcy..
Methods:We conducted a community-based cross-sectional study in two rural regions of Northern (Lianyungang) and Southern (Anqing) China from2008to2009. The Hcy levels were measured by enzyme immunoassay methods and the methylenetetrahydrofolate reductase (MTHFR)677C/T polymorphism was determined by high-throughput TaqMan allelic discrimination assay. Blood pressure (BP), body mass index (BMI) and other related demographic and lifestyle information were obtained through a standard questionnaire. Multivariate logistic regression model was performed to evaluate the associations of HHcy with the potential risk factors.
Results:A total of21,373hypertensive patients with the age range of45to75were available for the data analysis. Overall, the prevalence of HHcy (defined as Hcy≥10.0umol/L) was65.3%in males and43.0%in women in Chinese rural hypertensive patients. Gender, age, alcohol consumption, and MTHFR677C/T were associated with HHcy risk. On the logistic regression analysis, multivariate modeling further identified that among men, the odds ratios of HHcy were significantly increased from1.28to3.01with age groups from50-55to70-75yrs of age, compared with the youngest reference group (45-50yrs of age). Similarly the graded increase in odds ratios of HHcy from1.45to5.74were observed with increased age groups among women. Women in Anqing had a significantly increased prevalence of HHcy than in Lianyungang (OR=0.85;95%CI:0.68-1.07),but not men. The subjects with CT and TT genotype had significantly higher risks of HHcy both in men1.32(95%CI:1.19-1.47) and3.92(95%CI:3.39-4.52) Alcohol consumption is significantly associated was20%reduction in risk of HHcy compared with non-drinkers. Cigarette smoking is not significantly associated with HHcy in this population.
Conclusions:our study found that there was a high prevalence of HHcy in rural Chinese hypertensive patients and that the gender, age, and MTHFR677C/T were the major determinants of HHcy.
Objective:To evaluate the association of methylenetetrahydrofolate reductase (MTHFR) gene677C/T polymorphism with hyperhomocysteinemia (HHcy) in Chinese hypertensive patients.
Methods:We measured plasma tHcy level and677C/T genotype in1058Chinese hypertensive patients from four previous studies. We used10,15,20μmol/L as cut-off values for the definition of mild, modest, and severe HHcy, respectively, to evaluate the association of HHcy with MTHFR677C/T polymorphism and calculate the sensitivity and specificity. Logistic modelswere use to estimate the odds ratios of HHcy with MTHFR677C/T genotypes adjusting for potential confounders. The receiver operating characteristics of the models were evaluated with and without inclusion of age and gender.
Results:MTHFR677TT genotype is significantly and consistently associated with a higher Homocysteine across the four studies, with an increase in size ranging from38%to68%in the four studies and51%overall. The677C/T polymorphism independently explained about14%of the total variance of the normalized Hcy. The adjusted Odds Ratios for the TT genotype were3.9(95%CI:2.4-6.4),6.5(95%CI:4.0-10.6), and17.9(95%CI:8.4-38.1) for mild, modest, and severe HHcy, respectively. The predicting performance increased with HHcy severity, with sensitivity improved from31.0%for mild HHcy to70.3%for severe HHcy, and with specificity slightly decreased from85.4%to80.3%. Inclusion of gender and age as predictors significantly improves the sensitivity, especially for predicting mild HHcy.
Conclusion:With an excellent specificity and moderate sensitivity, the MTHFR677C/T polymorphism could be a useful screening marker for severe HHcy in hypertensive patients.
引文
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