TGF-β1基因SNPs及单体型分子标志与长沙汉族人群脑卒中的相关性研究

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英文题名：Research on the Relationship between the TGFB1 SNPs and Haplotypes and Stroke in Han People in Changsha Area 作者：梁辉 论文级别：博士 学科专业名称：神经病学 中文关键词：转换生长因子-β1 ; 单核甘酸多态性 ; 单体型 ; 脑梗死 ; 脑出血 英文关键词：TGF-β1 ; SNP ; cerebral infarction ; cerebral hemorrhage ; haplotype 学位年度：2010 导师：杨期东 学科代码：100204 学位授予单位：中南大学 论文提交日期：2010-05-01

摘要

研究背景和目的：
     通过20多年的临床流行病学研究,我们发现长沙是世界脑卒中的高发地区,其发病率呈缓慢上升趋势。受国家“八五”“九五”攻关课题资助,我们既往的研究发现长沙汉族人群在血压、血脂、血糖水平、体重指数这些传统的常规脑卒中危险因素无明显差异的前提下,湖南长沙地区汉族人群脑卒中的发病率仍较其他人群的发病率高。这表明除了传统的脑卒中危险因素之外,尚有其他因素影响了脑卒中的发生发展。目前认为脑卒中属于多基因疾病,遗传因素在脑卒中的发生发展中有着重要的作用。但目前脑卒中发生的具体遗传学机制仍不十分明确。我们的前期研究表明,apoH,apoB等与脂质代谢相关的基因多态现象与长沙汉族人群脑卒中相关。本研究力图寻找一种能够对脑卒中发生发展有着多重作用的基因。
     动脉粥样硬化是脑梗死和脑出血的一个共同病理过程,其形成和发展受到众多因素的影响。除了高血压、高脂血症、吸烟、饮酒等传统的脑卒中危险因素外,炎症细胞及其分泌的各种细胞因子与动脉粥样硬化的发生密切相关,如TNF、IL-6、IL-10等细胞因子和炎症介质均被证实参与了动脉粥样硬化的形成。
     TGF-β1是一种多功能细胞因子,与动脉粥样硬化斑块形成、高血压发生及血脂代谢紊乱等病理过程有关。研究表明TGFB1-800G>A、-509C＞T、+869T>C三个SNP参与了TGFB1表达的调节,可能影响到TGF-β1表达水平,且三者存在强连锁不平衡(LD, linkage disequilibrium)。有研究证实TGF-β1 SNP与动脉粥样硬化形成、高血压发生有关。基于以上事实,我们推测TGFB1 SNPs亦与长沙汉族人群脑卒中可能相关。经文献检索,目前尚无有关TGFB1 SNPs及单体型分子标志与脑卒中的相关研究。
     本研究旨在通过对长沙汉族人群TGFB1的多态分布规律的研究,从遗传流行病学的角度探讨TGFB1 SNPs与长沙汉族人群脑卒中的关系,揭示长沙汉族人群脑卒中高发病率的遗传学因素,并寻找可靠的脑卒中分子遗传标记；为筛选脑卒中的高危人群提供分子流行病学依据；同时也为脑卒中的基因功能学研究、治疗及预防奠定理论基础。
     方法：
     实验方法：应用聚合酶链反应(polymerase chain reaction,PCR)、限制性片段长度多态性(restriction fragment length polymorphism, RFLP)及DNA直接测序等方法对研究人群进行-800G>A、-509C＞T及+869T＞C基因分型。研究对象包括：①脑梗死(cerebral infarction, CI)患者186例,其中有高血压病史患者(定义为CI+H组)和无高血压病史患者(定义为CI+WH组)分别为75例和111例；有糖尿病病史的脑梗死及无糖尿病病史的脑梗死患者分别为39例和147例；无颈动脉粥样硬化斑块患者(定义为CI+WAP组)为26例,有颈动脉斑块形成患者(定义为CI+AP组)为160例,其中软斑、硬斑及混合斑形成患者分别为68、33、59例；有脑梗死家族史的患者(定义为FCI组)为132例,无脑梗死家族史的患者(定义为NFCI组)为54例；②脑出血(intracerebral hemorrhage, CH)患者202例,其中有高血压病史患者(定义为CH+H组)和无高血压病史患者(定义为CH+WH组)分别为125例和77例；有糖尿病病史的脑出血及无糖尿病病史的脑出血患者分别为30例和172例；无颈动脉粥样硬化斑块患者(定义为CH+WAP组)为60例,有颈动脉斑块成患者(定义为CH+AP组)为142例,其中软斑、硬斑及混合斑形成患者分别为60、32、50例；有脑出血家族史的患者(定义为FCH)为104例,无脑出血家族史的患者(定义为NFCH)为98例。③160例正常对照人群。
     统计学方法：应用SPSS13.0统计软件对所获得的实验数据进行相应的统计学处理：χ2检验分析各组基因型的Hardy-Weinberg平衡吻合度；计量资料两两比较采用t检验,两组以上比较采用ANOVA方差分析；计数资料采用χ2检验或Fisher确切概率法；建立logistic回归模型,将不同的脑卒中风险因素纳入模型,计量资料如血糖、血脂、年龄等进行分层分析,研究不同基因型对脑卒中发生风险的影响；利用SHEsis软件构建TGFB1单体型,并计算TGFB1-800G>A、-509C>T、+8691>C两两之间的D'和r2值,分析三者之间连锁不平衡(linkage disequilibrium)程度及不同单体型与脑卒中的关系。
     结果：
     1.脑梗死(cerebral infarction, CI)组和脑出血(cerebral hemorrhage,CH)组分别与对照组比较,-800G>A基因型及等位基因频率分布无显著差异(P＞0.05)；FCI、NFCI组分别与对照组比较,-800G>A基因型及等位基因频率分布无显著差异(P＞0.05)；-800G>A基因型及等位基因在各组内H亚组和WH亚组之间分布差异无统计学意义(P＞0.05)；-800G>A基因型及等位基因在各组内AP亚组和WAP亚组之间分布无显著差异(P＞0.05)；各组内GG基因型携带者较A等位基因携带者TC水平低(P＞0.01)；对照组中GG基因型携带者LDL-C平均水平较A等位基因携带者(P＜0.01)。
     2.CI组、CH组与对照组比较,-509C＞T和+869T＞C基因型及等位基因频率分布无统计学差异(P＞0.05),FCI与对照组比较,-509T等位基因携带者及+869C等位基因携带者频率较高(P<0.05),其中-509T携带者脑梗死的患病风险为对照组的1.557倍,+869C携带者脑梗死的患病风险为对照组的1.45倍。-509C>T和+869T＞C基因型及等位基因在各组内H亚组和WH亚组之间分布差异无统计学意义(P＞0.05)；-509C>T和+869T>C基因型及等位基因在各组内不同类型斑块亚组之间分布无显著差异(P＞0.05)；各组中不同类型-509C>T和+869T＞C基因型携带者血浆TG、TC、HDL-C、LDL-C无显著差异(P＞0.05)。
     3.CI组、CH组与对照组中,-509C>T与+869T＞C均存在强连锁不平衡关系,但与-800G>A连锁不平衡不明显(D'=0.098,r2=0.000；D'=0.019; r2=0.000)。-509C>T与+869T＞C构成两种主要单体型-509C/+869T和-509T/+869C。CI组和CH组分别与对照组比较,单体型频率分布无显著差异(P＞0.05)。
     结论：
     1. TGFB1-509C＞T及+869T>C与有脑梗死家族史的长沙汉族人群脑梗死发病可能相关,但与有脑出血家族史的长沙汉族人群脑出血发病无关,-509T和+869C等位基因可能是有脑梗死家族史的长沙汉族人群脑梗死发病的危险因子。
     2. TGFB1-800G＞A与血浆中TC水平可能相关,A等位基因可能是血浆TC水平增高的一个危险因素。
     3. TGFB1-509C＞T与+869T>C具有强的连锁关系,构成的单体型与长沙汉族人群脑梗死及脑出血发生无关。
Backgroud and objective:20 years of clinical epidemiological study showed that Changsha was the area of high stroke morbidity in the world. Supported by Eighth and Ninth Five-Year Plan, our previous studies showed that although there was no significant difference of the levels of blood lipid, blood glucose and BMI and other traditional risk factors, the stroke morbiditiy of Han population in Changsha area was higher than other areas. This suggests that there are some other factors in additional to the traditional risk factors. So far, it is known that stroke is multigenic disease, genetic factor play an important part in stroke. But the specific genetic machanisms of stroke are still unknown. Our previous studies showed that apoH, apoA and other gene polymorphism related with lipid metabolism were associated with the stroke of Han population in Changsha. In this study, we try to find a gene that have multiple action to stroke.
     Atherosclerosis is pathologic processes happen in both cerebral infarction and hemorrhage, which affected by many factors. Except for such as hypertension, hypelipidemia, smoking, drinking and other traditional factors, inflammatory cells and cytokine secreted by inflammatory cells are associated with the atherosclerosis. It has been proved that TNF, IL-6, IL-10 and other cytokines were related to this process.
     As a multifunctional cytokine, TGF-β1 is associated with atherosclerosis, hypertension and metabolism of lipid. Many studies showed TGFB1-800G>A,-509CT and+869T>C can regulate the expression of TGFB1 and the serum level of TGF-β1. The three SNPs are in linkage disequilibrium, they maybe affect the expression of TGFB1 togetherly. Some studies showed that the TGFB1 SNPs were related to the atherosclerosis and hypertension. Based on the fact, we hypothesis that these SNPs have association with stoke of Han population in Changsha area. Untill now, there is no related reports about the relationship between these SNPs and stroke in Changsha area.
     Through research of the TGFB1 SNP of Han population in Changsha area in this study, we will explore the relationship between the TGFB1 SNPs and the stroke in this area, reveal the genetic reason that the high morbidity of stroke in Changsha and find some dependable genetic marks of stroke. At the same time, it will provide molecular epidemiology evidence to screen the high-risk group of stroke and theoretical basis for gene function research, treatment and prevention of stroke.
     Method:The genotypes of 186 patients with cerebral infarction,202 patients with primary cerebral hemorrhage and 160 sex- and age-matched heath controls from Han population in Changsha area were detected by PCR-RFLP and direct DNA sequencing.χ2 test was used to check the Hardy-Weinberg balance of the genotype and compare the other numeration date. t test and AVONA analysis of variance was used to analysze the measurement date. Logistic regression analysis was used to evaluate the risk of onset of stroke of the subjects with different genotypes. The haplotypes and the linkage disequilibrium between TGFB1-800G>A,-509C＞T and +869T>C were analyzed by SHEsis (http://analysis.bio-x.cn/myAnalysis.php). D' and r2 are used to evaluate the linkage disequilibriuim.
     Result:
     1. The distribution of-800G>A gentypes and alleles is not different between CI growp and the control (P>0.05), no difference is observed between the CH group and the control group (P>0.05). There is no difference of the distribution of-800G>A genotype and allele between the H subgroup and the WH subgroup in CI group, and also in CH and control group. When the three groups were divided into AP and WAP subgroups respectively, no differences were found between the two subgroups in each group. GG carriers had lower serum levels of TC than the A allele carriers (P<0.01), while GG carriers had lower serum level of LDL-C than A allele carries in control group(P<0.01).
     2. The frequencies of the-509C＞T and +869T>C genotypes and alleles are not different between the CI and the control groups, no difference was found between the CH and the control groups(P＞0.05). But the frequencies of-509T and +869C carriers in FCI is higher than control group, the stroke prevalences of the-509T carriers in FCI is 1.557 multiples compared to the control group, while the +869C carriers in FCI is 1.45 multiples compared to the control group. There is no difference of the distribution of -509C>T and +869T>C genotypes and alleles between the H subgroup and the WH subgroup in CI group, no difference was found in CH and control group(P＞0.05). The frequencies of the-509C>T and +869T>C genotypes and alleles are not different among the subgroups with different atherosclerotic plaque(P>0.05). Serum levels of TG, TC, HDL-C and LDL-C of different-509C＞T and +869T>C genotypes carriers are not different(P>0.05).
     3.-509C>T and +869T>C are in high linkage disequilibrium, but they are in low linkage disequilibrium with-800G>A (D'=0.098, r2=0.000; D'=0.019; r2=0.000). Two major haplotypes of TGFB1 were found in the Han people in Changsha area, they are-509C/+869T and-509T/+869C. The frequencies of the two haplotypes are not different between the CI and control growps, and are not different between the CH and control groups.
     Conclusion:
     1. TGFB1-509C>T and +869T>C are associated with cerebral infarction of the people with a family history of cerebral infarction, but are not related to cerebral hemorrhage.-509T and +869C alleles are probably the risk factors of stroke of the people with history of cerebral infarction.
     2. TGFB1-800G>A is related to the serum level of TC. A allele are probably the risk factor of high TC levels.
     3.-509C＞T and+869T>C are in high linkage disequilibrium, but the haplotypes are not associated with both cerebral infarction and hemorrhage.

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