中国北方汉族人群CTH基因、HMOX1基因及HMOX2基因与原发性高血压的关联研究
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摘要
第一部分:血红素加氧酶基因多态性与原发性高血压的关联研究
研究背景和目的
血红素加氧酶(Heme oxygenase,HO)是催化血红素分解生成等摩尔一氧化碳(Carbon monoxide,CO)、铁和胆绿素的起始酶和限速酶,在体内以三种同工酶形式存在,分别是HO-1、HO-2和HO-3。HO-1为诱导型,广泛分布于全身组织细胞的微粒体内,脾、肝中含量最高,炎症细胞因子、激素和环磷酸腺苷(Cyclic adenosine monophosphate,cAMP)等均能诱导HO-1的生成;HO-2为构成型,于血管的内皮细胞及肌层天然表达,主要存在于内皮细胞和神经元内,脑组织和前列腺中含量最高;HO-3也是构成型,主要分布于脾脏和肝脏,是一个作用很弱的血红素催化剂。在这三种同工酶中,研究较多的是HO-1和HO-2。
肾脏在血压调节和高血压发生中发挥重要作用,肾脏功能异常可引起水钠潴留、肾血流量下降和肾小球滤过率下降,体内诱导生成HO-1可纠正这些异常变化。在动物模型中诱导生成HO-1可以保护横纹肌溶解症、顺铂肾毒性和肾毒性肾炎大鼠的肾脏功能。在急性肾衰和高血压中,HO的产物可提供保护性作用。另外有研究提示,血管紧张素Ⅱ(AngiotensinⅡ,AngⅡ)灌注可降低肾小球滤过率(Glomerular filtration rate,GFR),从而导致血压升高,随后即观察到HO-1表达上调,发挥细胞保护作用。这个研究证实HO-1在由肾脏功能异常导致的高血压中起到保护性作用。
氧化应激(Oxidative stress)参与了体内多种病理变化过程,包括高血压、动脉粥样硬化、心肌缺血和一些神经变性疾病。有研究证实,在脂蛋白E缺乏小鼠中给予血红素后,小鼠主动脉和肾脏中的HO-1表达增加,同时还原型烟酰胺腺嘌呤二核苷酸磷酸(Nicotinamide-adenine dinucleotide phosphate,NADPH)活性显著下降。此外,在高血压大鼠的肾髓质中诱导生成HO-1可降低血压水平。最近研究发现,HO-2敲除小鼠对肿瘤坏死因子-α引起的细胞凋亡非常敏感,抑制内源性生成HO-2可加重由肿瘤坏死因子-α诱发的氧化应激反应,说明内源性HO-2可抑制肿瘤坏死因子-α诱发的氧化应激反应,提供保护作用。这些研究结果提示HO可能通过调节机体的氧化应激状态参与体内血压的调控和高血压的发生发展。
以上这些证据提示HO-1和HO-2可能参与了原发性高血压的发生发展。HO-1和HO-2的编码基因分别是HMOX1和HMOX2,目前关于这两个基因多态与高血压关系的研究尚较少。本研究采用病例对照设计,探讨在中国北方汉族人群中,HMOX1基因和HMOX2基因多态是否与原发性高血压关联,同时应用多因子降维方法(Multifactor dimensionality reduction,MDR)分析HMOX1基因和HMOX2基因多态在高血压的发生中是否存在交互作用。
材料和方法
所有研究对象的DNA样本和临床资料均来自亚洲国际心血管疾病协作研究(International collaborative study of cardiovascular disease in Asia,InterASIA)的中国部分。为了检测出高血压病例和血压正常者之间可能的遗传差异和提高关联分析的把握度,我们从InterASIA人群中选择了503例血压水平为收缩压(Systolicblood pressure,SBP)≥160mmHg和/或舒张压(Diastolic blood pressure,DBP)≥100mmHg的高血压患者和490例年龄、性别匹配的正常血压对照(SBP＜140mmHg且DBP＜90mmHg)。参加者均接受标准的问卷调查,调查内容包括疾病史、家族史、吸烟与饮酒史和药物使用情况,并测量血压、身高、体重、腰围及臀围以及脂质水平等各项生化指标。所有研究对象均为汉族且无血缘关系。研究中排除了有继发性高血压、冠心病、糖尿病、脑卒中、严重肝肾疾病或甲状腺疾病病史以及恶性肿瘤的患者。采用标签单核苷酸多态(Tagging SNP,tagSNP)策略,在中国汉族人群中少见等位基因频率(Minor allele frequency,MAF)≥0.05的所有SNP中,HMOX1基因筛选出3个标签SNP位点,分别是rs8140669 T/A多态、rs9607267 T/C多态和rs2071749 G/A多态;HMOX2基因筛选出2个标签SNP位点,分别是rs4786500 T/C多态和rs9921781 C/T多态。采用聚合酶链反应和限制性片断长度多态性方法对这5个SNP位点进行基因分型。病例组和对照组间基因型的分布和等位基因频率的比较采用卡方检验;采用非条件Logistic回归分析检验多态位点与表型的独立关联,以上分析过程由SPSS 13.0来完成。采用Haplo.stats软件包分析单体型、双体型与原发性高血压的关系。
结果
病例组和对照组的性别、年龄、吸烟率和饮酒率均无显著性差异。所有5个标签SNP位点均符合Hardy-Weinberg平衡。
单点分析结果提示,病例组中HMOX1基因的rs9607267位点CC基因型频率高于对照组,校正其它影响因素后,rs9607267位点CC基因型个体高血压发病危险是该位点其它基因型个体的1.41倍(95%Cl:1.02-1.95,P=0.040)。数量性状分析结果也显示rs9607267位点CC基因型个体血压水平显著高于该位点其它基因型患者,校正其它影响因素后,rs9607267位点CC基因型个体与其它基因型个体比较,收缩压水平升高4.7 mmHg,舒张压水平升高2.8 mmHg,差别有统计学意义。单体型分析结果显示,携带HMOX1基因rs9607267位点C等位基因的单体型Hap3(T-C-G)与血压水平相关,校正其它影响因素后,该单体型的EH发病危险为对照单体型(Hapl,T-T-G)的1.44倍(95%Cl:1.04-2.01,P=0.029)。此外,没有观察到HMOX2基因与原发性高血压之间的关联。多因子降维(MDR)分析也没有发现HMOX1基因和HMOX2基因在原发性高血压的发生中存在交互作用。
结论
中国北方汉族人群中HMOX1基因多态可能与血压水平及原发性高血压相关联,该关联有待在其他人群中进一步研究证实。
第二部分:中国北方汉族人群胱硫醚-γ-裂解酶基因多态性与原发性高血压的关联研究
研究背景和目的
高血压是导致中风、心肌梗塞和肾衰患者死亡的重要原因,目前已成为危害人类健康的主要公共卫生问题。在过去的几十年间,对高血压病理机制进行了大量的研究,但由于高血压是一种遗传因素和环境因素共同作用引起的复杂性疾病,存在多基因决定性、遗传异质性、外显不全、表型模糊等诸多因素,阻碍了对其遗传机制的深入研究,以致这些研究结果在不同人群中的重复性较差,甚至在同种族人群亦有差异,关于高血压的发病机制仍不明确。
内源性硫化氢(Hydrogen sulfide,H_2S)是继一氧化氮(Nitric oxide,NO)和CO之后的第三种气体信号分子,在调节血管舒张程度等多方面具有与NO及CO非常相似的特性。内源性H_2S主要来自于体内的同型半胱氨酸,在硫化作用下生成半胱氨酸,然后半胱氨酸在胱硫醚-β-合成酶(Cystathionineβ-synthase,CBS)和胱硫醚-γ-裂解酶(Cystathionineγ-lyase,CSE)作用下生成H_2S。CBS主要分布于神经系统,而CSE主要表达于肝脏、肾脏和血管平滑肌。研究发现,高血压大鼠胸主动脉中CSE表达水平和活性均低于对照组。此外,实施腹主动脉-下腔静脉分流术后的大鼠肺动脉CSE mRNA表达水平与正常对照组比较明显下调,这提示CSE可能与高血压的发生相关。
CSE的编码基因为CTH,在其第12外显子处存在一个常见错义突变1364G＞T(rs1021737),该多态使CTH基因编码的第403位氨基酸由丝氨酸(Serine,Ser)变为异亮氨酸(Isoleucine,Ile)。研究发现该多态与血清同型半胱氨酸浓度相关,而同型半胱氨酸能增强氧化应激的反应程度,刺激血管平滑肌细胞增殖并改变血管壁弹性蛋白的特性,从而参与高血压的发生与发展。这些结果提示我们CTH基因有可能通过调控血清同型半胱氨酸浓度来参与血压调节和高血压的发生发展。目前尚没有关于CTH基因多态与原发性高血压的关联研究报道。本研究采用病例对照研究设计,在中国北方汉族人群中探讨CSE编码基因CTH多态是否与原发性高血压(Essential hypertension,EH)相关。
材料和方法
所有研究对象的DNA样本和临床资料均来自亚洲国际心血管疾病协作研究(International collaborative study of cardiovascular disease in Asia,InterASIA)的中国部分。我们选择了503例血压水平为SBP≥160mmHg和/或DBP≥100mmHg的高血压患者和490例年龄、性别匹配的正常血压对照者(SBP＜140mmHg且DBP＜90mmHg)进行研究。参加者均接受标准的问卷调查,调查内容包括疾病个人史、家族史、吸烟与饮酒史和药物使用情况,并测量血压、身高、体重、腰围、臀围以及脂质水平等各项生化指标。所有研究对象均为汉族且无血缘关系。本研究排除了有继发性高血压、冠心病、糖尿病、脑卒中、严重肝肾疾病或甲状腺疾病病史以及恶性肿瘤的患者。采用单核苷酸多态位点功能分析和选择工具(Function analysis and selection tool for single nucleotide polymorphisms,FastSNP)进行SNP位点选择。在中国汉族人群中少见等位基因频率(Minor allelefrequency,MAF)≥0.05的所有SNP位点中,根据FastSNP功能预测结果,选择了2个CTH基因潜在的功能位点:rs482843位点A/G多态和rs1021737位点G/T多态。基因分型方法PCR-RFLP方法。病例组和对照组间基因型分布和等位基因频率的比较采用卡方检验,采用非条件Logistic回归分析检验多态位点与表型的独立关联,以上分析过程由SPSS 13.0来完成。采用Haplo.stats软件包分析单体型、双体型与原发性高血压的关系。
结果
病例组和对照组的性别、年龄、吸烟率和饮酒率均无显著性差异。CTH基因rs482843位点和rs1021737位点均符合Hardy-Weinberg平衡。病例组和对照组中这两个多态位点的基因型分布和等位基因频率没有显著差别(P值均＞0.05)。在逐步回归分析中,校正年龄、性别等协变量后,也没有发现CTH基因rs482843位点和rs1021737位点与高血压相关。此外,在校正协变量前和校正协变量后均没有发现可以增加或降低高血压危险的单体型或双体型。
结论
我们的研究没有观察到中国北方汉族人群的CTH基因rs482843 A/G多态和rs1021737 G/T多态与原发性高血压相关。关于CTH基因与原发性高血压的关系尚需在其他人群中进行重复验证,同时需要进一步的功能研究证据。
Section 1: Association study of the heme oxygenase genes with essential hypertension in northern Chinese Han population
Background
Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, with release of free iron and carbon monoxide (CO). HO exists as three isoenzymes, HO-1, HO-2, and HO-3, each encoded by a different gene. HO-1 is an inducible isoform that may be induced through the use of various pharmaceutical agents. HO-2 is constitutively expressed in blood vessels, endothelium, testis and most other tissues and its levels are relatively unaffected by factors inducing HO-1. HO-3 is constitutively expressed at low levels and is not active in heme metabolism. HO-1 and HO-2 are both viewed as playing a major role in the heme breakdown and are alike in terms of mechanism of heme oxidation, cofactor, and substrate specificities.
Renal abnormalities leading to hypertension consist of reduced excertion of sodium and water, decreased renal blood flow, and decreased glomerular filtration. Such abnormalities can be corrected by inducing HO-1 activity. HO-1 induction has also been shown to exert a protective effect on renal function in animal models of rhabdomyolysis, cisplatin nephrotoxicity, and nephrotoxic nephritis. In another study, Ang II infusion decreased glomerular filtration rate (GFR), which led to hypertension. HO-1 upregulation naturally followed and provided a cytoprotective effect. Once again, the evidence suggests that HO-1 has a protective effect against the development of hypertension.
Oxidative stress is a state in which excess reactive oxygen species overwhelm endogenous antioxidant systems and it plays an important role in the development of hypertension through the disturbance of the delicate balance of endothelium-derived Vasoactive factors caused by these reactions. Induction of HO-1 in vivo can suppress NADPH oxidase-derived oxidative stress. It had also been reported that the induction of HO-1 may lower blood pressure (BP) and superoxide production in the renal medulla of angiotensin II hypertensive mice. Recently, Basuroy et al. reported that the HO-2 provided endogenous protection against oxidative stress. Therefore, we presume that the HO-1 and HO-2 may act as regulator of oxidative stress and play a part in the pathogenesis of hypertension.
The HO-1 and HO-2 were encoded by the heme oxygenase gene-1 (HMOX1) and the heme oxygenase gene-2 (HMOX2) respectively. This study aimed to assess the effect of these two genes on EH in northern Chinese Han population.
Methods
All the DNA samples and clinical data of the studied subjects were selected from the International collaborative study of cardiovascular disease in Asia (InterASIA in China). To maximize the potential genetic differences and statistical power for the association analysis, we selected 993 subjects as a subsample containing 503 hypertensive patients (systolic blood pressure (SBP)≥160mmHg and/or diastolic blood pressure (DBP)≥100mmHg, or self-reported current treatment for hypertension with antihypertensive medications) and 490 age-, gender- and area-matched normotensive controls (SBP<140mm Hg and DBP<90mmHg) from the main study population. With the whole gene-based tagging single nucleotide polymorphism (SNP) approach, three SNPs of the HMOX1 gene and two SNPs of the HMOX2 gene were selected as the tagSNPs by the Haploview Tagger program. These tagSNPs were genotyped in 503 cases and 490 controls. The differences in clinical characteristics between cases and controls were assessed by a t-test for quantitative variables and chi-square test for qualitative ones. The frequencies of the alleles and genotypes between cases and controls were compared by the chi-square test. To test the association between genotypes and EH, a stepwise logistic regression was also conducted to adjust for covariates including age, gender, body mass index (BMI), glucose (Glu), TG, TC, HDL-C, creatinine (Cr), smoking and drinking status. Hardy-Weinberg equilibrium (HWE) was assessed by Fisher's exact test using the program HWE. The program Haplo.stats was used to investigate the relationship between the haplotypes and EH. The program of multifactor-dimensionality reduction (MDR) was used to test for potential gene-gene interactions.
Results
Three SNPs, rs8140669, rs9607267 and rs2071749, of the HMOX1 gene and two SNPs, rs4786500 and rs9921781 of the HMOX2 gene were selected as the tagging SNPs. None of these five SNPs deviated significantly from the HWE in the case or control group. Single SNP analyses indicated that the frequency of rs9607267 of HMOX1 gene in case group was higher than that in control group. Subjects with rs9607267 CC genotype had the higher EH risk than subjects with TT or TC genotype (adjusted OR=1.41, 95%CI: 1.02-1.95, P=0.040). In addition, the CC genotype of rs9607267 was associated with high blood pressure level. After adjusted for covariates, systolic blood pressure and diastolic blood pressure in CC genotype carrier were higher than that in TT or TC genotype (increased by 4.7 mmHg and 2.8 mmHg, respectively). In haplotype analysis, we found the Hap3 (T-C-G) of the HMOX1 gene which carried the rs9607267 C allele was associated with blood pressure level and might increase the risk of EH (adjusted OR=1.44, 95%CI: 1.04-2.01, P=0.029). No association was observed between the HMOX2 gene and EH. The multifactor-dimensionality reduction (MDR) analysis results did not show any interaction between the HMOX1 gene and HMOX2 gene underlying the development of hypertension.
Conclusion
The genetic variants of the HMOX1 gene might contribute to the risk of the EH in north Chinese Han population and other studies with large sample size and function study were needed to confirm the association between the HMOX genes and EH.
Section 2: Relationship between cystathionineγ-lyase gene polymorphisms and essential hypertension in Northern Chinese Han population
Background
Hypertension is an important worldwide public health challenge and it affects approximately 25% of the adult population worldwide. There is a direct relationship between the risks of stroke, heart attack, heart failure, kidney disease and the severity of hypertension. It is widely believed that essential hypertension (EH) is a complex disease influenced by multiple factors. Although numerous physiological alterations have been studied in hypertensive individuals, the etiopathogenisis of hypertension is still not well elucidated.
The endogenous production of hydrogen sulfide (H2S) and its physiological functions, including membrane hyperpolarization and smooth muscle cell relaxation, place this gas in the family of gas transmitters, together with nitric oxide (NO) and carbon monoxide (CO). Two enzymes, cystathionineβ-synthase (CBS) and cystathionineγ-lyase (CSE), are responsible for the endogenous production of H_2S in mammalian tissues. The CBS is a predominant H2S-generating enzyme in the brain and nervous system, and the CSE is mainly expressed in liver, kidney, and vascular smooth muscles. The gene expression and the activity of the CSE in thoracic aorta were suppressed in hypertension rats, and the expression of the CSE mRNA was down-regulated in the pulmonary hypertension rats. Therefore, it is possible that the CSE, which is encoded by CTH gene, may participate in the regulation of BP and even in the development of EH. In addition, the polymorphism of rs1021737 in CTH gene was associated with variation in plasma homocysteine level, which plays a role in the pathogenesis of essential hypertension. However, no study to date has assessed the relationship between the CTH gene variations and hypertension.
In this study, we performed a case-control study to investigate whether the CTH gene was associated with the EH in a northern Chinese Han population.
Methods
All the DNA samples and clinical data of the studied subjects were selected from the International collaborative study of cardiovascular disease in Asia (InterASIA in China). To maximize the potential genetic differences and statistical power for the association analysis, we selected 993 subjects as a subsample containing 503 hypertensive patients (systolic blood pressure (SBP)≥160mmHg and/or diastolic blood pressure (DBP)≥100mmHg, or self-reported current treatment for hypertension with antihypertensive medications) and 490 age-, gender- and area-matched normotensive controls (SBP< 140mm Hg and DBP<90mm Hg) from the main study population. Based on the FASTSNP, a web server to identify putative functional single nucleotide polymorphisms (SNPs) of genes, we selected two SNPs (rs482843 and rs1021737) in the CTH gene for genotyping. Genotyping was performed by the polymerase chain reaction and restriction fragment length polymorphism method (PCR-RFLP). The frequencies of the alleles and genotypes between cases and controls were compared by the chi-square test. The program Haplo.stats was used to investigate the relationship between the haplotypes and EH.
Results
These two SNPs were in Hardy-Weinberg Equilibrium in both cases and controls. Genotype distributions and allele frequencies of them did not significantly differ between cases and controls (all P>0.05). In the stepwise logistic regression analysis, we did not observe their association with hypertension either. In addition, none of the four estimated haplotypes or diplotypes significantly increased or decreased the risk of hypertension before or after adjustment for several known risk factors.
Conclusion
This present study suggested that the SNPs rs482843 and rsl021737 of the CTH gene were not associated with essential hypertension in Northern Chinese Han population. However, replications in other populations and further functional studies are still necessary to clarify the role of the CTH gene in the pathogenesis of EH.
研究背景和目的
血红素加氧酶(Heme oxygenase,HO)是催化血红素分解生成等摩尔一氧化碳(Carbon monoxide,CO)、铁和胆绿素的起始酶和限速酶,在体内以三种同工酶形式存在,分别是HO-1、HO-2和HO-3。HO-1为诱导型,广泛分布于全身组织细胞的微粒体内,脾、肝中含量最高,炎症细胞因子、激素和环磷酸腺苷(Cyclic adenosine monophosphate,cAMP)等均能诱导HO-1的生成;HO-2为构成型,于血管的内皮细胞及肌层天然表达,主要存在于内皮细胞和神经元内,脑组织和前列腺中含量最高;HO-3也是构成型,主要分布于脾脏和肝脏,是一个作用很弱的血红素催化剂。在这三种同工酶中,研究较多的是HO-1和HO-2。
肾脏在血压调节和高血压发生中发挥重要作用,肾脏功能异常可引起水钠潴留、肾血流量下降和肾小球滤过率下降,体内诱导生成HO-1可纠正这些异常变化。在动物模型中诱导生成HO-1可以保护横纹肌溶解症、顺铂肾毒性和肾毒性肾炎大鼠的肾脏功能。在急性肾衰和高血压中,HO的产物可提供保护性作用。另外有研究提示,血管紧张素Ⅱ(AngiotensinⅡ,AngⅡ)灌注可降低肾小球滤过率(Glomerular filtration rate,GFR),从而导致血压升高,随后即观察到HO-1表达上调,发挥细胞保护作用。这个研究证实HO-1在由肾脏功能异常导致的高血压中起到保护性作用。
氧化应激(Oxidative stress)参与了体内多种病理变化过程,包括高血压、动脉粥样硬化、心肌缺血和一些神经变性疾病。有研究证实,在脂蛋白E缺乏小鼠中给予血红素后,小鼠主动脉和肾脏中的HO-1表达增加,同时还原型烟酰胺腺嘌呤二核苷酸磷酸(Nicotinamide-adenine dinucleotide phosphate,NADPH)活性显著下降。此外,在高血压大鼠的肾髓质中诱导生成HO-1可降低血压水平。最近研究发现,HO-2敲除小鼠对肿瘤坏死因子-α引起的细胞凋亡非常敏感,抑制内源性生成HO-2可加重由肿瘤坏死因子-α诱发的氧化应激反应,说明内源性HO-2可抑制肿瘤坏死因子-α诱发的氧化应激反应,提供保护作用。这些研究结果提示HO可能通过调节机体的氧化应激状态参与体内血压的调控和高血压的发生发展。
以上这些证据提示HO-1和HO-2可能参与了原发性高血压的发生发展。HO-1和HO-2的编码基因分别是HMOX1和HMOX2,目前关于这两个基因多态与高血压关系的研究尚较少。本研究采用病例对照设计,探讨在中国北方汉族人群中,HMOX1基因和HMOX2基因多态是否与原发性高血压关联,同时应用多因子降维方法(Multifactor dimensionality reduction,MDR)分析HMOX1基因和HMOX2基因多态在高血压的发生中是否存在交互作用。
材料和方法
所有研究对象的DNA样本和临床资料均来自亚洲国际心血管疾病协作研究(International collaborative study of cardiovascular disease in Asia,InterASIA)的中国部分。为了检测出高血压病例和血压正常者之间可能的遗传差异和提高关联分析的把握度,我们从InterASIA人群中选择了503例血压水平为收缩压(Systolicblood pressure,SBP)≥160mmHg和/或舒张压(Diastolic blood pressure,DBP)≥100mmHg的高血压患者和490例年龄、性别匹配的正常血压对照(SBP＜140mmHg且DBP＜90mmHg)。参加者均接受标准的问卷调查,调查内容包括疾病史、家族史、吸烟与饮酒史和药物使用情况,并测量血压、身高、体重、腰围及臀围以及脂质水平等各项生化指标。所有研究对象均为汉族且无血缘关系。研究中排除了有继发性高血压、冠心病、糖尿病、脑卒中、严重肝肾疾病或甲状腺疾病病史以及恶性肿瘤的患者。采用标签单核苷酸多态(Tagging SNP,tagSNP)策略,在中国汉族人群中少见等位基因频率(Minor allele frequency,MAF)≥0.05的所有SNP中,HMOX1基因筛选出3个标签SNP位点,分别是rs8140669 T/A多态、rs9607267 T/C多态和rs2071749 G/A多态;HMOX2基因筛选出2个标签SNP位点,分别是rs4786500 T/C多态和rs9921781 C/T多态。采用聚合酶链反应和限制性片断长度多态性方法对这5个SNP位点进行基因分型。病例组和对照组间基因型的分布和等位基因频率的比较采用卡方检验;采用非条件Logistic回归分析检验多态位点与表型的独立关联,以上分析过程由SPSS 13.0来完成。采用Haplo.stats软件包分析单体型、双体型与原发性高血压的关系。
结果
病例组和对照组的性别、年龄、吸烟率和饮酒率均无显著性差异。所有5个标签SNP位点均符合Hardy-Weinberg平衡。
单点分析结果提示,病例组中HMOX1基因的rs9607267位点CC基因型频率高于对照组,校正其它影响因素后,rs9607267位点CC基因型个体高血压发病危险是该位点其它基因型个体的1.41倍(95%Cl:1.02-1.95,P=0.040)。数量性状分析结果也显示rs9607267位点CC基因型个体血压水平显著高于该位点其它基因型患者,校正其它影响因素后,rs9607267位点CC基因型个体与其它基因型个体比较,收缩压水平升高4.7 mmHg,舒张压水平升高2.8 mmHg,差别有统计学意义。单体型分析结果显示,携带HMOX1基因rs9607267位点C等位基因的单体型Hap3(T-C-G)与血压水平相关,校正其它影响因素后,该单体型的EH发病危险为对照单体型(Hapl,T-T-G)的1.44倍(95%Cl:1.04-2.01,P=0.029)。此外,没有观察到HMOX2基因与原发性高血压之间的关联。多因子降维(MDR)分析也没有发现HMOX1基因和HMOX2基因在原发性高血压的发生中存在交互作用。
结论
中国北方汉族人群中HMOX1基因多态可能与血压水平及原发性高血压相关联,该关联有待在其他人群中进一步研究证实。
第二部分:中国北方汉族人群胱硫醚-γ-裂解酶基因多态性与原发性高血压的关联研究
研究背景和目的
高血压是导致中风、心肌梗塞和肾衰患者死亡的重要原因,目前已成为危害人类健康的主要公共卫生问题。在过去的几十年间,对高血压病理机制进行了大量的研究,但由于高血压是一种遗传因素和环境因素共同作用引起的复杂性疾病,存在多基因决定性、遗传异质性、外显不全、表型模糊等诸多因素,阻碍了对其遗传机制的深入研究,以致这些研究结果在不同人群中的重复性较差,甚至在同种族人群亦有差异,关于高血压的发病机制仍不明确。
内源性硫化氢(Hydrogen sulfide,H_2S)是继一氧化氮(Nitric oxide,NO)和CO之后的第三种气体信号分子,在调节血管舒张程度等多方面具有与NO及CO非常相似的特性。内源性H_2S主要来自于体内的同型半胱氨酸,在硫化作用下生成半胱氨酸,然后半胱氨酸在胱硫醚-β-合成酶(Cystathionineβ-synthase,CBS)和胱硫醚-γ-裂解酶(Cystathionineγ-lyase,CSE)作用下生成H_2S。CBS主要分布于神经系统,而CSE主要表达于肝脏、肾脏和血管平滑肌。研究发现,高血压大鼠胸主动脉中CSE表达水平和活性均低于对照组。此外,实施腹主动脉-下腔静脉分流术后的大鼠肺动脉CSE mRNA表达水平与正常对照组比较明显下调,这提示CSE可能与高血压的发生相关。
CSE的编码基因为CTH,在其第12外显子处存在一个常见错义突变1364G＞T(rs1021737),该多态使CTH基因编码的第403位氨基酸由丝氨酸(Serine,Ser)变为异亮氨酸(Isoleucine,Ile)。研究发现该多态与血清同型半胱氨酸浓度相关,而同型半胱氨酸能增强氧化应激的反应程度,刺激血管平滑肌细胞增殖并改变血管壁弹性蛋白的特性,从而参与高血压的发生与发展。这些结果提示我们CTH基因有可能通过调控血清同型半胱氨酸浓度来参与血压调节和高血压的发生发展。目前尚没有关于CTH基因多态与原发性高血压的关联研究报道。本研究采用病例对照研究设计,在中国北方汉族人群中探讨CSE编码基因CTH多态是否与原发性高血压(Essential hypertension,EH)相关。
材料和方法
所有研究对象的DNA样本和临床资料均来自亚洲国际心血管疾病协作研究(International collaborative study of cardiovascular disease in Asia,InterASIA)的中国部分。我们选择了503例血压水平为SBP≥160mmHg和/或DBP≥100mmHg的高血压患者和490例年龄、性别匹配的正常血压对照者(SBP＜140mmHg且DBP＜90mmHg)进行研究。参加者均接受标准的问卷调查,调查内容包括疾病个人史、家族史、吸烟与饮酒史和药物使用情况,并测量血压、身高、体重、腰围、臀围以及脂质水平等各项生化指标。所有研究对象均为汉族且无血缘关系。本研究排除了有继发性高血压、冠心病、糖尿病、脑卒中、严重肝肾疾病或甲状腺疾病病史以及恶性肿瘤的患者。采用单核苷酸多态位点功能分析和选择工具(Function analysis and selection tool for single nucleotide polymorphisms,FastSNP)进行SNP位点选择。在中国汉族人群中少见等位基因频率(Minor allelefrequency,MAF)≥0.05的所有SNP位点中,根据FastSNP功能预测结果,选择了2个CTH基因潜在的功能位点:rs482843位点A/G多态和rs1021737位点G/T多态。基因分型方法PCR-RFLP方法。病例组和对照组间基因型分布和等位基因频率的比较采用卡方检验,采用非条件Logistic回归分析检验多态位点与表型的独立关联,以上分析过程由SPSS 13.0来完成。采用Haplo.stats软件包分析单体型、双体型与原发性高血压的关系。
结果
病例组和对照组的性别、年龄、吸烟率和饮酒率均无显著性差异。CTH基因rs482843位点和rs1021737位点均符合Hardy-Weinberg平衡。病例组和对照组中这两个多态位点的基因型分布和等位基因频率没有显著差别(P值均＞0.05)。在逐步回归分析中,校正年龄、性别等协变量后,也没有发现CTH基因rs482843位点和rs1021737位点与高血压相关。此外,在校正协变量前和校正协变量后均没有发现可以增加或降低高血压危险的单体型或双体型。
结论
我们的研究没有观察到中国北方汉族人群的CTH基因rs482843 A/G多态和rs1021737 G/T多态与原发性高血压相关。关于CTH基因与原发性高血压的关系尚需在其他人群中进行重复验证,同时需要进一步的功能研究证据。
Section 1: Association study of the heme oxygenase genes with essential hypertension in northern Chinese Han population
Background
Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, with release of free iron and carbon monoxide (CO). HO exists as three isoenzymes, HO-1, HO-2, and HO-3, each encoded by a different gene. HO-1 is an inducible isoform that may be induced through the use of various pharmaceutical agents. HO-2 is constitutively expressed in blood vessels, endothelium, testis and most other tissues and its levels are relatively unaffected by factors inducing HO-1. HO-3 is constitutively expressed at low levels and is not active in heme metabolism. HO-1 and HO-2 are both viewed as playing a major role in the heme breakdown and are alike in terms of mechanism of heme oxidation, cofactor, and substrate specificities.
Renal abnormalities leading to hypertension consist of reduced excertion of sodium and water, decreased renal blood flow, and decreased glomerular filtration. Such abnormalities can be corrected by inducing HO-1 activity. HO-1 induction has also been shown to exert a protective effect on renal function in animal models of rhabdomyolysis, cisplatin nephrotoxicity, and nephrotoxic nephritis. In another study, Ang II infusion decreased glomerular filtration rate (GFR), which led to hypertension. HO-1 upregulation naturally followed and provided a cytoprotective effect. Once again, the evidence suggests that HO-1 has a protective effect against the development of hypertension.
Oxidative stress is a state in which excess reactive oxygen species overwhelm endogenous antioxidant systems and it plays an important role in the development of hypertension through the disturbance of the delicate balance of endothelium-derived Vasoactive factors caused by these reactions. Induction of HO-1 in vivo can suppress NADPH oxidase-derived oxidative stress. It had also been reported that the induction of HO-1 may lower blood pressure (BP) and superoxide production in the renal medulla of angiotensin II hypertensive mice. Recently, Basuroy et al. reported that the HO-2 provided endogenous protection against oxidative stress. Therefore, we presume that the HO-1 and HO-2 may act as regulator of oxidative stress and play a part in the pathogenesis of hypertension.
The HO-1 and HO-2 were encoded by the heme oxygenase gene-1 (HMOX1) and the heme oxygenase gene-2 (HMOX2) respectively. This study aimed to assess the effect of these two genes on EH in northern Chinese Han population.
Methods
All the DNA samples and clinical data of the studied subjects were selected from the International collaborative study of cardiovascular disease in Asia (InterASIA in China). To maximize the potential genetic differences and statistical power for the association analysis, we selected 993 subjects as a subsample containing 503 hypertensive patients (systolic blood pressure (SBP)≥160mmHg and/or diastolic blood pressure (DBP)≥100mmHg, or self-reported current treatment for hypertension with antihypertensive medications) and 490 age-, gender- and area-matched normotensive controls (SBP<140mm Hg and DBP<90mmHg) from the main study population. With the whole gene-based tagging single nucleotide polymorphism (SNP) approach, three SNPs of the HMOX1 gene and two SNPs of the HMOX2 gene were selected as the tagSNPs by the Haploview Tagger program. These tagSNPs were genotyped in 503 cases and 490 controls. The differences in clinical characteristics between cases and controls were assessed by a t-test for quantitative variables and chi-square test for qualitative ones. The frequencies of the alleles and genotypes between cases and controls were compared by the chi-square test. To test the association between genotypes and EH, a stepwise logistic regression was also conducted to adjust for covariates including age, gender, body mass index (BMI), glucose (Glu), TG, TC, HDL-C, creatinine (Cr), smoking and drinking status. Hardy-Weinberg equilibrium (HWE) was assessed by Fisher's exact test using the program HWE. The program Haplo.stats was used to investigate the relationship between the haplotypes and EH. The program of multifactor-dimensionality reduction (MDR) was used to test for potential gene-gene interactions.
Results
Three SNPs, rs8140669, rs9607267 and rs2071749, of the HMOX1 gene and two SNPs, rs4786500 and rs9921781 of the HMOX2 gene were selected as the tagging SNPs. None of these five SNPs deviated significantly from the HWE in the case or control group. Single SNP analyses indicated that the frequency of rs9607267 of HMOX1 gene in case group was higher than that in control group. Subjects with rs9607267 CC genotype had the higher EH risk than subjects with TT or TC genotype (adjusted OR=1.41, 95%CI: 1.02-1.95, P=0.040). In addition, the CC genotype of rs9607267 was associated with high blood pressure level. After adjusted for covariates, systolic blood pressure and diastolic blood pressure in CC genotype carrier were higher than that in TT or TC genotype (increased by 4.7 mmHg and 2.8 mmHg, respectively). In haplotype analysis, we found the Hap3 (T-C-G) of the HMOX1 gene which carried the rs9607267 C allele was associated with blood pressure level and might increase the risk of EH (adjusted OR=1.44, 95%CI: 1.04-2.01, P=0.029). No association was observed between the HMOX2 gene and EH. The multifactor-dimensionality reduction (MDR) analysis results did not show any interaction between the HMOX1 gene and HMOX2 gene underlying the development of hypertension.
Conclusion
The genetic variants of the HMOX1 gene might contribute to the risk of the EH in north Chinese Han population and other studies with large sample size and function study were needed to confirm the association between the HMOX genes and EH.
Section 2: Relationship between cystathionineγ-lyase gene polymorphisms and essential hypertension in Northern Chinese Han population
Background
Hypertension is an important worldwide public health challenge and it affects approximately 25% of the adult population worldwide. There is a direct relationship between the risks of stroke, heart attack, heart failure, kidney disease and the severity of hypertension. It is widely believed that essential hypertension (EH) is a complex disease influenced by multiple factors. Although numerous physiological alterations have been studied in hypertensive individuals, the etiopathogenisis of hypertension is still not well elucidated.
The endogenous production of hydrogen sulfide (H2S) and its physiological functions, including membrane hyperpolarization and smooth muscle cell relaxation, place this gas in the family of gas transmitters, together with nitric oxide (NO) and carbon monoxide (CO). Two enzymes, cystathionineβ-synthase (CBS) and cystathionineγ-lyase (CSE), are responsible for the endogenous production of H_2S in mammalian tissues. The CBS is a predominant H2S-generating enzyme in the brain and nervous system, and the CSE is mainly expressed in liver, kidney, and vascular smooth muscles. The gene expression and the activity of the CSE in thoracic aorta were suppressed in hypertension rats, and the expression of the CSE mRNA was down-regulated in the pulmonary hypertension rats. Therefore, it is possible that the CSE, which is encoded by CTH gene, may participate in the regulation of BP and even in the development of EH. In addition, the polymorphism of rs1021737 in CTH gene was associated with variation in plasma homocysteine level, which plays a role in the pathogenesis of essential hypertension. However, no study to date has assessed the relationship between the CTH gene variations and hypertension.
In this study, we performed a case-control study to investigate whether the CTH gene was associated with the EH in a northern Chinese Han population.
Methods
All the DNA samples and clinical data of the studied subjects were selected from the International collaborative study of cardiovascular disease in Asia (InterASIA in China). To maximize the potential genetic differences and statistical power for the association analysis, we selected 993 subjects as a subsample containing 503 hypertensive patients (systolic blood pressure (SBP)≥160mmHg and/or diastolic blood pressure (DBP)≥100mmHg, or self-reported current treatment for hypertension with antihypertensive medications) and 490 age-, gender- and area-matched normotensive controls (SBP< 140mm Hg and DBP<90mm Hg) from the main study population. Based on the FASTSNP, a web server to identify putative functional single nucleotide polymorphisms (SNPs) of genes, we selected two SNPs (rs482843 and rs1021737) in the CTH gene for genotyping. Genotyping was performed by the polymerase chain reaction and restriction fragment length polymorphism method (PCR-RFLP). The frequencies of the alleles and genotypes between cases and controls were compared by the chi-square test. The program Haplo.stats was used to investigate the relationship between the haplotypes and EH.
Results
These two SNPs were in Hardy-Weinberg Equilibrium in both cases and controls. Genotype distributions and allele frequencies of them did not significantly differ between cases and controls (all P>0.05). In the stepwise logistic regression analysis, we did not observe their association with hypertension either. In addition, none of the four estimated haplotypes or diplotypes significantly increased or decreased the risk of hypertension before or after adjustment for several known risk factors.
Conclusion
This present study suggested that the SNPs rs482843 and rsl021737 of the CTH gene were not associated with essential hypertension in Northern Chinese Han population. However, replications in other populations and further functional studies are still necessary to clarify the role of the CTH gene in the pathogenesis of EH.
引文
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14. Rodrigo, R., W. Passalacqua, J. Araya, et al., Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension. J Cardiovasc Pharmacol,2003. 42(4): p. 453-61.
15. Datla, S.R., G.J. Dusting, T.A. Mori, et al., Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress. Hypertension, 2007. 50(4): p.636-42.
16. Vera, T., S. Kelsen, L.L. Yanes, et al., HO-1 induction lowers blood pressure and superoxide production in the renal medulla of angiotensin II hypertensive mice. Am J Physiol Regul Integr Comp Physiol, 2007. 292(4): p. R1472-8.
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