GH-IGF-I轴基因多态性及环境因素与缺血性脑卒中的分子流行病学研究
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摘要
目的近年来，越来越多的研究表明GH-IGF-I轴可能与缺血性脑卒中的发生密切相关。但是关于本轴基因多态性与环境因素之间交互作用对缺血性脑卒中的影响，国内外罕见报道。本研究探讨GH-IGF-I轴家族基因的多态性及环境因素与缺血性脑卒中发病的关联，为脑卒中的预防和临床治疗提供理论依据。
方法按照全国第四届脑血管病会议缺血性脑卒中诊断标准，开展以医院为基础的1：1配对病例-对照研究。所有的研究对象来自于深圳三大医院，病例和对照按年龄≤5岁、性别、民族相同进行匹配，共收集384对。使用统一的流行病学调查表对所有研究对象进行调查。用Taqman MGB荧光定量PCR技术及单碱基延伸技术等检测基因型。运用单因素及多因素logistic回归分析基因多态性与缺血性脑卒中之间的关系，运用Phasev2．0软件和Haploview v4．1软件进行单体型分析，运用分类树分析方法构建缺血性脑卒中发病风险的预测模型，用多因子降维法分析基因的多态位点之间的潜在交互作用。
结果1．PDGF-D基因的rs7950273携带GG基因型在对照组中所占的比例比病例组高，调整混杂因素后GG基因型是缺血性脑卒中的保护因素，OR值为0．499，95％CI为0．28-0．89，并且GG基因型的胆固醇均值为1．76mmol／l高于CG+CC基因型的1．67mmol／l，胆固醇均值在不同的基因型中有统计学差异(P=0．022)；
2．IGF-I基因的rs6220，rs1520220和rs7965399多态性与缺血性脑卒中的发病无关，其中rs6220和rs1520220存在完全连锁(|D’|=0.97，R~2=0．94)。而调整混杂因素后CArepeat的17／17是缺血性脑卒中的危险因素(OR 3．83，95％CI为1．12-13．01)，尤其在年龄＞55岁的个体中(OR 4．65，95％CI 1．60-13．51)；
3．运用标签SNP的策略，选出GHR基因的10个标签SNP，并探讨其基因型与缺血性脑卒中发病的关系，发现rs6451627基因多态性与缺血性脑卒中的发病紧密相关；
4．本研究应用分类树模型得到6个重要解释变量，即高血压病史、糖尿病病史、冠心病史、吸烟、饮酒及GHR的rs6451627多态性，多因子降维法提示GHR基因的rs6451627与rs12187996存在交互作用。
结论高血压病史是缺血性脑卒中首要的危险因素，糖尿病史、冠心病史、吸烟、饮酒是缺血性脑卒中的密切相关因素，长期有效地控制高血压、糖尿病，积极防治冠心病，限制饮酒和吸烟和拥有健康的生活方式是预防和降低缺血性脑卒中发病的主要措施。遗传因素中GH-IGF-I轴对缺血性脑卒中的发生起重要作用，对筛查缺血性脑卒中的高危人群有重要的意义。
Objectives In recent years, more and more evidences have shown that GH-IGF-I axismay be associated with the occurrence of ischemic stroke. However, in China and othercountries, there were few studies about the association between the interaction of genepolymorphisms of GH-IGF-I and environmental factors with incidence of ischemic stroke.This study investigated their relationship for providing a theoretical basis for clinicalprevention and treatment.
Methods According to the diagnostic criteria of ischemic stroke on the Fourth NationalConference, one 1:1 matched case-control study was performed based on hospital. Allsubjects came from three general hospitals in Shenzhen. The 384 controls matched the 384cases with the same gender and ethnic group, and differring within 5 years age. The cases andcontrols were interviewed using the same questionnaire. Genotypes were determined by usingTaqman MGB genotyping and single base extension assay. Univariate test and multiplelogistic regression models were used to explore the association between the polymorphismsand ischemic stroke. Haplotype analyses of these polymorphisms were performed using Phasev2.0 software and Haploview v4.1 software. Classification tree model was applied to build upthe risk model for ischemic stroke, and multifactor dimensionality reduction was used toevaluate the interaction among the studied polymorphisms.
Results 1.For rs7950273 polymorphism, the frequency of carrying GG genotype ofPDGF-D in controls was higher than that in cases. After adjusting confounding factors, GGgenotype of PDGF-D was a protective factor for ischemic stroke (OR 0.499, 95% CI0.28-0.89). The mean level of cholesterol in the individuals carrying GG genotype was higher than carrying CG/CC genotype, and there was significant difference between GG genotypeand CG/CC genotypes(P=0.002);
2.There were no association between rs6220, rs1520220 and rs7965399 of IGF-I geneand the incidence of ischemic stroke. Rs6220 and rs1520220 were in high linkagedisequilibrium (|D'|=0.97, r~2=0.94). After adjusting the confounding factors, the CA repeat17/17 genotype appeared to be a risk factor for ischemic stroke (OR 3.83, 95% CI 1.12-13.01),especially in the old who were more than 55-year-old (OR 4.65, 95% CI 1.60-13.51);
3. Based on tagging SNP strategy, 10 tagging SNPs were choosed from all SNPs of GHRgene and were to evaluate the relationship between the genotype of the tagging SNPs and theoccurrence of ischemic stroke. Then the association between the genotype of rs6451627 andthe occurrence of ischemic stroke was found;
4. In this study, six important explanatory variables, namely, history of hypertension,history of diabetes, history of heart disease, smoking, drinking and rs6451627 of GHR wereselected from classification tree model. There was a strong interaction between rs6451627 andrs12187996 of GHR gene under multi-factor dimensionality reduction method.
Conelusions History of hypertension is the primary and most important risk factor forischemic stroke, so be diabetes, coronary heart disease, smoking and alcohol intaking. Thus,the main measures to prevent and reduce the incidence of ischemic stroke are to controlhypertension, diabetes and coronary heart disease actively, limit alcohol intaking and smokingto have a healthy life-style. Genetic factors in the GH-IGF-I axis which play an important roleon the occurrence of ischemic stroke will lead to availably screen of high-risk groups ofischemic stroke.
方法按照全国第四届脑血管病会议缺血性脑卒中诊断标准，开展以医院为基础的1：1配对病例-对照研究。所有的研究对象来自于深圳三大医院，病例和对照按年龄≤5岁、性别、民族相同进行匹配，共收集384对。使用统一的流行病学调查表对所有研究对象进行调查。用Taqman MGB荧光定量PCR技术及单碱基延伸技术等检测基因型。运用单因素及多因素logistic回归分析基因多态性与缺血性脑卒中之间的关系，运用Phasev2．0软件和Haploview v4．1软件进行单体型分析，运用分类树分析方法构建缺血性脑卒中发病风险的预测模型，用多因子降维法分析基因的多态位点之间的潜在交互作用。
结果1．PDGF-D基因的rs7950273携带GG基因型在对照组中所占的比例比病例组高，调整混杂因素后GG基因型是缺血性脑卒中的保护因素，OR值为0．499，95％CI为0．28-0．89，并且GG基因型的胆固醇均值为1．76mmol／l高于CG+CC基因型的1．67mmol／l，胆固醇均值在不同的基因型中有统计学差异(P=0．022)；
2．IGF-I基因的rs6220，rs1520220和rs7965399多态性与缺血性脑卒中的发病无关，其中rs6220和rs1520220存在完全连锁(|D’|=0.97，R~2=0．94)。而调整混杂因素后CArepeat的17／17是缺血性脑卒中的危险因素(OR 3．83，95％CI为1．12-13．01)，尤其在年龄＞55岁的个体中(OR 4．65，95％CI 1．60-13．51)；
3．运用标签SNP的策略，选出GHR基因的10个标签SNP，并探讨其基因型与缺血性脑卒中发病的关系，发现rs6451627基因多态性与缺血性脑卒中的发病紧密相关；
4．本研究应用分类树模型得到6个重要解释变量，即高血压病史、糖尿病病史、冠心病史、吸烟、饮酒及GHR的rs6451627多态性，多因子降维法提示GHR基因的rs6451627与rs12187996存在交互作用。
结论高血压病史是缺血性脑卒中首要的危险因素，糖尿病史、冠心病史、吸烟、饮酒是缺血性脑卒中的密切相关因素，长期有效地控制高血压、糖尿病，积极防治冠心病，限制饮酒和吸烟和拥有健康的生活方式是预防和降低缺血性脑卒中发病的主要措施。遗传因素中GH-IGF-I轴对缺血性脑卒中的发生起重要作用，对筛查缺血性脑卒中的高危人群有重要的意义。
Objectives In recent years, more and more evidences have shown that GH-IGF-I axismay be associated with the occurrence of ischemic stroke. However, in China and othercountries, there were few studies about the association between the interaction of genepolymorphisms of GH-IGF-I and environmental factors with incidence of ischemic stroke.This study investigated their relationship for providing a theoretical basis for clinicalprevention and treatment.
Methods According to the diagnostic criteria of ischemic stroke on the Fourth NationalConference, one 1:1 matched case-control study was performed based on hospital. Allsubjects came from three general hospitals in Shenzhen. The 384 controls matched the 384cases with the same gender and ethnic group, and differring within 5 years age. The cases andcontrols were interviewed using the same questionnaire. Genotypes were determined by usingTaqman MGB genotyping and single base extension assay. Univariate test and multiplelogistic regression models were used to explore the association between the polymorphismsand ischemic stroke. Haplotype analyses of these polymorphisms were performed using Phasev2.0 software and Haploview v4.1 software. Classification tree model was applied to build upthe risk model for ischemic stroke, and multifactor dimensionality reduction was used toevaluate the interaction among the studied polymorphisms.
Results 1.For rs7950273 polymorphism, the frequency of carrying GG genotype ofPDGF-D in controls was higher than that in cases. After adjusting confounding factors, GGgenotype of PDGF-D was a protective factor for ischemic stroke (OR 0.499, 95% CI0.28-0.89). The mean level of cholesterol in the individuals carrying GG genotype was higher than carrying CG/CC genotype, and there was significant difference between GG genotypeand CG/CC genotypes(P=0.002);
2.There were no association between rs6220, rs1520220 and rs7965399 of IGF-I geneand the incidence of ischemic stroke. Rs6220 and rs1520220 were in high linkagedisequilibrium (|D'|=0.97, r~2=0.94). After adjusting the confounding factors, the CA repeat17/17 genotype appeared to be a risk factor for ischemic stroke (OR 3.83, 95% CI 1.12-13.01),especially in the old who were more than 55-year-old (OR 4.65, 95% CI 1.60-13.51);
3. Based on tagging SNP strategy, 10 tagging SNPs were choosed from all SNPs of GHRgene and were to evaluate the relationship between the genotype of the tagging SNPs and theoccurrence of ischemic stroke. Then the association between the genotype of rs6451627 andthe occurrence of ischemic stroke was found;
4. In this study, six important explanatory variables, namely, history of hypertension,history of diabetes, history of heart disease, smoking, drinking and rs6451627 of GHR wereselected from classification tree model. There was a strong interaction between rs6451627 andrs12187996 of GHR gene under multi-factor dimensionality reduction method.
Conelusions History of hypertension is the primary and most important risk factor forischemic stroke, so be diabetes, coronary heart disease, smoking and alcohol intaking. Thus,the main measures to prevent and reduce the incidence of ischemic stroke are to controlhypertension, diabetes and coronary heart disease actively, limit alcohol intaking and smokingto have a healthy life-style. Genetic factors in the GH-IGF-I axis which play an important roleon the occurrence of ischemic stroke will lead to availably screen of high-risk groups ofischemic stroke.
引文
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