PDE4D基因多态性与河南汉族人群缺血性脑血管病的相关性研究
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摘要
背景与目的：
缺血性脑血管病(ischemic cerebrovascular disease ICVD)是遗传因素和环境因素共同作用而导致的一种多基因遗传病,发病机制异常复杂,其发病率、致残率及死亡率高,给个人、家庭及社会带来沉重的负担。我国属于缺血性脑血管病的高发国家,并且发病率呈逐年上升的趋势。对现有的已知危险因素如高血压、糖尿病、高血脂、动脉粥样硬化、心律不齐、吸烟等进行良好控制后,许多患者仍不可避免地发生脑血管病,这促使学者们不断寻找新的脑血管病的危险因素,特别是从基因水平确定不同个体对脑血管病的易感性。
2003年,卒中基因解码科学小组人员在冰岛人群中发现了与家族性缺血性脑血管病相关的基因：磷酸二酯酶4D (phosphodiesterase4D PDE4D)基因与脑动脉粥样硬化的发生发展有关。PDE4D为第二信使环磷酸腺苷(eyclicAdenosineMonophosphate cAMP)特异性PDE, PDE4D可通过其水平和活性的变化影响细胞内cAMP水平,cAMP水平影响血管细胞的增殖和移行,参与动脉粥样硬化的进程,从而增加心脑血管疾病的发病风险。该基因和以往认识的与糖尿病、血脂代谢异常、高血压等脑血管病危险因素的相关基因是不同的,其对缺血性脑血管病具有独立的致病作用,被认为是新发现的卒中候选基因。
为了进一步探讨PDE4D基因多态性与ICVD的相关性,本研究利用聚合酶链反应—限制性片段长度多态性(Polymerase chain reaction restriction-fragment length polymorphism PCR-RFLP)技术,在河南汉族人群中对PDE4Drs918592和rs2910829位点多态性进行检测,研究其分布情况,并进一步探讨该位点多态性与ICVD相关性。从而为脑血管病的预防研究提供理论依据。
研究对象：
1.病例组
随机选取2007年4月至2010年5月在河南省二甲以上医院神经内科住院的缺血性脑血管病患者400例,其中男238例,女162例,年龄51.15.±10.16。所有病例均经临床检查(生化检验、病史、CT或MRI)确诊,所有病例均符合WHO缺血性脑卒中的定义(急性发生的血管或血液异常导致脑部血液循环障碍而发生的神经功能缺损综合征),头颅CT或MRI排除出血,症状持续24小时(以上)
2.对照组
随机选取同期体检健康的随机个体400例,无冠心病、脑血管病和其他周围血管病史,其中男235例,女165例,年龄46.00±12.04岁。
以上两组研究对象均是在研究对象知情同意的原则下进行。均为河南地区汉族人,饮食结构相似,各研究对象之间排除癫痫、接受器官移植、癌症及肝肾功能不全等疾病患者。
研究方法：
取研究对象外周静脉血5 mL加EDTA抗凝,用常规的酚／氯仿法提取DNA。设计合成引物,PCR仪扩增获得目的片段,用ApaLI、SspI限制性内切酶酶切,2.5%琼脂糖凝胶电泳检测基因型,在紫外分析凝胶成像仪上观察基因型并照相分析。
统计学处理：
所有数据处理均采用SPSS15.0统计软件包进行统计学处理,ICVD组与正常人群之间基因型频率和等位基因频率的差异用x2检验,并计算比数比(Odds Ratio, OR)及95%可信区间(CI),以估计基因突变对疾病发生的相对危险度,检验水准a=0.05。用Hardy-Weinberg (HWE)平衡检验估计群体调查资料的可靠性。HWE平衡检验应用SHEsis软件(P>0.05)；单倍体型分析采用Shesis软件。
结果：
1.在河南汉族人群中,PDE4D基因rs918592和rs2910829位点基因型频率的分布均符合Hardy-weinberg平衡(P>0.05),具有良好的人群代表性。
2.在河南汉族人群中,PDE4Drs918592位点在ICVD组和对照组相比,基因型频率和等位基因频率差异有统计学意义(P<0.05)；进行性别分层分析结果显示,在男性ICVD组与对照组之间差异也有统计学意义(P<0.05)。
3.对PDE4Drs918592和rs2910829位点按照年龄进行分层分析,rs918592和rs2910829位点在小于等于45岁的ICVD组与对照组间差异均有统计学意义(P<0.05)；rs918592位点在大于45岁的ICVD组与对照组之间差异有统计学意义(P<0.05)。
4.rs918592位点在显性、隐性模式下和ICVD相关(P<0.05),在叠加模式下其AA基因型和ICVD相关(P<0.05)。
5.在河南汉族人群中,对PDE4Drs918592A/G和rs2910829 C/T两个位点在ICVD组与对照组间进行单倍型分析,G-T和A-T单倍型差异有统计学意义(P<0.05)。
6.在河南汉族正常人群中PDE4D rs918592和rs2910829位点多态性存在种族差异。
结论：
1.相对风险分析发现,PDE4D rs918592 A等位基因可能是河南汉族人群缺血性脑血管病的遗传危险因子,并且这种危险性在男性中表现明显。
2.相对风险分析发现,PDE4D rs2910829 T等位基因可能是河南汉族年龄小于等于45岁人群缺血性脑血管病的遗传危险因子。
3.PDE4D G-T单倍型和PDE4DA-T单倍型可能是河南汉族人群ICVD发病的遗传危险因子。
Background and Aims:
Ischemic cerebrovascular disease(ICVD)is a polygenic inheritable disease caused mainly by the interaction of genetic and environmental factors. ICVD has been putting great burden on individuals, families and society because of its extremely complicated pathogenesis and extraordinarily high morbidity, deformity and mortality. China is one of the countries with high morbidity of ICVD and its incident rate is becoming increasingly high. Although the known danger factors like hypertension, diabetes, hyperlipemia, atherosclerosis, arrhythmia as well as smoking have been well controlled, many patients still inevitably suffer from ICVD, which arouses researchers'focus on finding out new danger factors of ICVD, especially determining the susceptibility of ICVD to different individuals from gene level.
In 2003, Gretarsdott et al. found phosphodiesterase 4D (PDE4D) associated with familial inherited ICVD was related to the progression of atherosclerosis. PDE4D is specific to hydrolyze cyclic adenosine monophosphat(cAMP) whose existing level affects the proliferation and migration of angiocellulars. Thus PDE4D is able to control the existing level of cAMP through its existing level and activity and further to affect the process of atherosclerosis. Therefore, PDE4D has certain effect on the invasion risk of ICVD. PDE4D gene is different from the genes associated with the invasion risk of ICVD such as diabetes, abnormal metabolism of blood lipid and hypertension due to its independent effect on the pathogenesis of ICVD. Thus PDE4D gene is so far considered as the only canditate gene associated with stroke newly discovered. Therefore PDE4D gene has been arousing the interest of researchers around the world, but the research results are not so identical.
PDE4D is firstly considered as the candidate gene of ICVD universally. To further investigate the relationship between PDE4D gene polymorphism and ICVD, polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP) was adopted to detect the polymorphism of PDE4D rs918592 and PDE4D rs2910829 in han population of Henan. The distribution of rs918592 and rsRS2910829 and the relationship between ICVD and rs918592 as well as rs2910829 were investigated to provide theory evidence for the prevention of ICVD.
Study population:
1 Patients 400 cases as patient group with ischemic cerebrovascular disease in departments of neurology in Henan province hospitals were enrolled from December 2007 to 2010.There were 238male and 162 female with an average of 51.15.±10.16 years. All of them are Han population.
2 Controls 400unrelated heathy controls were selected from subjects in outpatient department who underwent regular check-up examination.235 of them were male and 165 were female with an averageof 46.00±12.04years.The cases of control group had no history of CHD, EH and DM.All of them are Han population.
Methods:
5ml EDTA-anticoagulated Peripheral blood were obtained from ICVD patients and control. Genomic DNA was extracted by phenol-chloroform extraction method and its content was determined by ultraviolet spectrophotometer.Using the primers, we performed polymerase chain reaction(PCR) amplification and refined frequence length polymorphism(RFLP).These products were electrophoresed on 2.5% agarose gels, and DNA was visualized by ethidium bromide straining.
Statistical analysis:
The frequence of the alleles and genotypes were counted and compared by the Chi-square test. Hardy-weinberg equilibrium was confirmed with the X2 test. Odds Rations(OR) and 95% confidence intervals(95%C1) were used to estimate the risk association to the genotype. All statistical procedures were performed with SPSS13.0 software package. P value<0.05 was taken as statistical significant.
Results:
1. The genotype distribution of the PDE4D rs918592 and rs2910829 polymorphism was compatible with the Hardy-Weinberg equilibrium in the ICVD group and control group.
2. The frequency of the PDE4D rs918592 between ICVD group and control group exist strong difference, further,in accordance with the sex classification analysis, there was also significant difference in the genotype or allele frequency in male.
3. In accordance with the age classification analysis, there was significant difference in the genotype or allele frequency of PDE4D rs2910829 in less than 45 years of age.
4. The AA genotype of rs918592 is assoeiated with ICVD in an additive mode (P<0.05),rs918592 in dominant or recessive mode(P<0.05).
5. The linkage analysis showed that:G-T and A-T haplotypes between cases and controls exist significant differences.
6. The frequencies of PDE4D rs918592 and rs2910829 might exist difference in ethnic groups.
Conclusion:
1. Relative risk analysis showed that it carrying PDE4D rs918592 A allele may increase the risk of ischemic cerebrovascular disease, especially in male patients.
2. Relative risk analysis showed that it may increase the risk of less than 45 years of age ischemic cerebrovascular disease carrying PDE4D rs2910829T allele.
3. It suggestde that PDE4D G-T and A-T haplotypes are risk factors for Henan Han population.
缺血性脑血管病(ischemic cerebrovascular disease ICVD)是遗传因素和环境因素共同作用而导致的一种多基因遗传病,发病机制异常复杂,其发病率、致残率及死亡率高,给个人、家庭及社会带来沉重的负担。我国属于缺血性脑血管病的高发国家,并且发病率呈逐年上升的趋势。对现有的已知危险因素如高血压、糖尿病、高血脂、动脉粥样硬化、心律不齐、吸烟等进行良好控制后,许多患者仍不可避免地发生脑血管病,这促使学者们不断寻找新的脑血管病的危险因素,特别是从基因水平确定不同个体对脑血管病的易感性。
2003年,卒中基因解码科学小组人员在冰岛人群中发现了与家族性缺血性脑血管病相关的基因：磷酸二酯酶4D (phosphodiesterase4D PDE4D)基因与脑动脉粥样硬化的发生发展有关。PDE4D为第二信使环磷酸腺苷(eyclicAdenosineMonophosphate cAMP)特异性PDE, PDE4D可通过其水平和活性的变化影响细胞内cAMP水平,cAMP水平影响血管细胞的增殖和移行,参与动脉粥样硬化的进程,从而增加心脑血管疾病的发病风险。该基因和以往认识的与糖尿病、血脂代谢异常、高血压等脑血管病危险因素的相关基因是不同的,其对缺血性脑血管病具有独立的致病作用,被认为是新发现的卒中候选基因。
为了进一步探讨PDE4D基因多态性与ICVD的相关性,本研究利用聚合酶链反应—限制性片段长度多态性(Polymerase chain reaction restriction-fragment length polymorphism PCR-RFLP)技术,在河南汉族人群中对PDE4Drs918592和rs2910829位点多态性进行检测,研究其分布情况,并进一步探讨该位点多态性与ICVD相关性。从而为脑血管病的预防研究提供理论依据。
研究对象：
1.病例组
随机选取2007年4月至2010年5月在河南省二甲以上医院神经内科住院的缺血性脑血管病患者400例,其中男238例,女162例,年龄51.15.±10.16。所有病例均经临床检查(生化检验、病史、CT或MRI)确诊,所有病例均符合WHO缺血性脑卒中的定义(急性发生的血管或血液异常导致脑部血液循环障碍而发生的神经功能缺损综合征),头颅CT或MRI排除出血,症状持续24小时(以上)
2.对照组
随机选取同期体检健康的随机个体400例,无冠心病、脑血管病和其他周围血管病史,其中男235例,女165例,年龄46.00±12.04岁。
以上两组研究对象均是在研究对象知情同意的原则下进行。均为河南地区汉族人,饮食结构相似,各研究对象之间排除癫痫、接受器官移植、癌症及肝肾功能不全等疾病患者。
研究方法：
取研究对象外周静脉血5 mL加EDTA抗凝,用常规的酚／氯仿法提取DNA。设计合成引物,PCR仪扩增获得目的片段,用ApaLI、SspI限制性内切酶酶切,2.5%琼脂糖凝胶电泳检测基因型,在紫外分析凝胶成像仪上观察基因型并照相分析。
统计学处理：
所有数据处理均采用SPSS15.0统计软件包进行统计学处理,ICVD组与正常人群之间基因型频率和等位基因频率的差异用x2检验,并计算比数比(Odds Ratio, OR)及95%可信区间(CI),以估计基因突变对疾病发生的相对危险度,检验水准a=0.05。用Hardy-Weinberg (HWE)平衡检验估计群体调查资料的可靠性。HWE平衡检验应用SHEsis软件(P>0.05)；单倍体型分析采用Shesis软件。
结果：
1.在河南汉族人群中,PDE4D基因rs918592和rs2910829位点基因型频率的分布均符合Hardy-weinberg平衡(P>0.05),具有良好的人群代表性。
2.在河南汉族人群中,PDE4Drs918592位点在ICVD组和对照组相比,基因型频率和等位基因频率差异有统计学意义(P<0.05)；进行性别分层分析结果显示,在男性ICVD组与对照组之间差异也有统计学意义(P<0.05)。
3.对PDE4Drs918592和rs2910829位点按照年龄进行分层分析,rs918592和rs2910829位点在小于等于45岁的ICVD组与对照组间差异均有统计学意义(P<0.05)；rs918592位点在大于45岁的ICVD组与对照组之间差异有统计学意义(P<0.05)。
4.rs918592位点在显性、隐性模式下和ICVD相关(P<0.05),在叠加模式下其AA基因型和ICVD相关(P<0.05)。
5.在河南汉族人群中,对PDE4Drs918592A/G和rs2910829 C/T两个位点在ICVD组与对照组间进行单倍型分析,G-T和A-T单倍型差异有统计学意义(P<0.05)。
6.在河南汉族正常人群中PDE4D rs918592和rs2910829位点多态性存在种族差异。
结论：
1.相对风险分析发现,PDE4D rs918592 A等位基因可能是河南汉族人群缺血性脑血管病的遗传危险因子,并且这种危险性在男性中表现明显。
2.相对风险分析发现,PDE4D rs2910829 T等位基因可能是河南汉族年龄小于等于45岁人群缺血性脑血管病的遗传危险因子。
3.PDE4D G-T单倍型和PDE4DA-T单倍型可能是河南汉族人群ICVD发病的遗传危险因子。
Background and Aims:
Ischemic cerebrovascular disease(ICVD)is a polygenic inheritable disease caused mainly by the interaction of genetic and environmental factors. ICVD has been putting great burden on individuals, families and society because of its extremely complicated pathogenesis and extraordinarily high morbidity, deformity and mortality. China is one of the countries with high morbidity of ICVD and its incident rate is becoming increasingly high. Although the known danger factors like hypertension, diabetes, hyperlipemia, atherosclerosis, arrhythmia as well as smoking have been well controlled, many patients still inevitably suffer from ICVD, which arouses researchers'focus on finding out new danger factors of ICVD, especially determining the susceptibility of ICVD to different individuals from gene level.
In 2003, Gretarsdott et al. found phosphodiesterase 4D (PDE4D) associated with familial inherited ICVD was related to the progression of atherosclerosis. PDE4D is specific to hydrolyze cyclic adenosine monophosphat(cAMP) whose existing level affects the proliferation and migration of angiocellulars. Thus PDE4D is able to control the existing level of cAMP through its existing level and activity and further to affect the process of atherosclerosis. Therefore, PDE4D has certain effect on the invasion risk of ICVD. PDE4D gene is different from the genes associated with the invasion risk of ICVD such as diabetes, abnormal metabolism of blood lipid and hypertension due to its independent effect on the pathogenesis of ICVD. Thus PDE4D gene is so far considered as the only canditate gene associated with stroke newly discovered. Therefore PDE4D gene has been arousing the interest of researchers around the world, but the research results are not so identical.
PDE4D is firstly considered as the candidate gene of ICVD universally. To further investigate the relationship between PDE4D gene polymorphism and ICVD, polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP) was adopted to detect the polymorphism of PDE4D rs918592 and PDE4D rs2910829 in han population of Henan. The distribution of rs918592 and rsRS2910829 and the relationship between ICVD and rs918592 as well as rs2910829 were investigated to provide theory evidence for the prevention of ICVD.
Study population:
1 Patients 400 cases as patient group with ischemic cerebrovascular disease in departments of neurology in Henan province hospitals were enrolled from December 2007 to 2010.There were 238male and 162 female with an average of 51.15.±10.16 years. All of them are Han population.
2 Controls 400unrelated heathy controls were selected from subjects in outpatient department who underwent regular check-up examination.235 of them were male and 165 were female with an averageof 46.00±12.04years.The cases of control group had no history of CHD, EH and DM.All of them are Han population.
Methods:
5ml EDTA-anticoagulated Peripheral blood were obtained from ICVD patients and control. Genomic DNA was extracted by phenol-chloroform extraction method and its content was determined by ultraviolet spectrophotometer.Using the primers, we performed polymerase chain reaction(PCR) amplification and refined frequence length polymorphism(RFLP).These products were electrophoresed on 2.5% agarose gels, and DNA was visualized by ethidium bromide straining.
Statistical analysis:
The frequence of the alleles and genotypes were counted and compared by the Chi-square test. Hardy-weinberg equilibrium was confirmed with the X2 test. Odds Rations(OR) and 95% confidence intervals(95%C1) were used to estimate the risk association to the genotype. All statistical procedures were performed with SPSS13.0 software package. P value<0.05 was taken as statistical significant.
Results:
1. The genotype distribution of the PDE4D rs918592 and rs2910829 polymorphism was compatible with the Hardy-Weinberg equilibrium in the ICVD group and control group.
2. The frequency of the PDE4D rs918592 between ICVD group and control group exist strong difference, further,in accordance with the sex classification analysis, there was also significant difference in the genotype or allele frequency in male.
3. In accordance with the age classification analysis, there was significant difference in the genotype or allele frequency of PDE4D rs2910829 in less than 45 years of age.
4. The AA genotype of rs918592 is assoeiated with ICVD in an additive mode (P<0.05),rs918592 in dominant or recessive mode(P<0.05).
5. The linkage analysis showed that:G-T and A-T haplotypes between cases and controls exist significant differences.
6. The frequencies of PDE4D rs918592 and rs2910829 might exist difference in ethnic groups.
Conclusion:
1. Relative risk analysis showed that it carrying PDE4D rs918592 A allele may increase the risk of ischemic cerebrovascular disease, especially in male patients.
2. Relative risk analysis showed that it may increase the risk of less than 45 years of age ischemic cerebrovascular disease carrying PDE4D rs2910829T allele.
3. It suggestde that PDE4D G-T and A-T haplotypes are risk factors for Henan Han population.
引文
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29. Bevan S, Dichgans M, Gschwendtner A, et al.Variation in the PDE4D gene and ischemic stroke risk:a systematic review and meta-analysis on 5200 cases and 6600 controls[J]. Stroke,2008,39(7):1966-71.
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1. Ren J, Zhao D, Liu J, et al. Relationship between serum non-high-density lipoprotein cholesterol and incidence of cardiovascular disease [J]. Zhonghua Xin Xue Guan Bing Za Zhi,2010,38(10):934-8.
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5. Yang Y, Ferec C, Mura C. SNP and haplotype analysis reveals new HFE variants associated with iron overload trait [J]. Hum Mutat,2011,32(4):E2104-17.
6. Pang H, Hauser M, Minvielle S. Pathway-based identification of SNPs predictive of survival [J]. Eur J Hum Genet,2011,2:568-8.
7. Barbazuk WB, Schnable PS. SNP discovery by transcriptome pyrosequencing[J]. Methods Mol Biol,2011,729:225-46.
8. Tuefferd M, de Bondt A, Van den Wyngaert I, et al. Microarray Profiling of DNA Extracted from FFPE Tissues Using SNP 6.0 Affymetrix Platform [J]. Methods Mol Biol,2011, 724:147-60.
9. Mandoiu Ⅱ, Prajescu C. High-throughput SNP genotyping by SBE/SBH[J]. IEEE Trans Nanobioscience,2007,6(1):28-35.
10. Owens WB. Blood pressure control in acute cerebrovascular disease [J]. J Clin Hypertens (Greenwich),2011,13(3):205-11.
11. Liu X, Wang W, Tang Z, et al. Clinical study of PTAS therapy for patients with ischemia cerebrovascular disease caused by artery stenosis [J]. J Huazhong Univ Sci Technolog Med Sci,2011,31(1):67-72.
12. Yang L, Zhang B, Yin L, et al. Tanshinone IIA Prevented Brain Iron Dyshomeostasis in Cerebral Ischemic Rats [J]. Cell Physiol Biochem,2011,27(l):23-30.
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