痰湿体质基础研究及其与代谢综合征相关性的探索
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摘要
目的:挖掘传统中医理论中痰湿体质相关内容,总结近现代研究成果,完善中医痰湿体质理论;研究痰湿体质单核苷酸多态性(single nucleotide polymorphisms,SNP)和拷贝数变异(copy number variation,CNV)特征,以探索痰湿体质的内在分子机制;探索痰湿体质与代谢综合征的相关性,深化痰湿体质理论与应用研究,为防治其相关疾病提供依据。
方法:采用传统文献梳理与现代文献分析的方法,进行中医痰湿体质理论研究。应用Affymetrix公司GeneChip Mapping 500K Array检测技术,比较分析痰湿体质与平和体质者单核苷酸多态性和拷贝数变异差异,在分子水平探索痰湿体质的特征。采用临床流行病学、医学统计学方法分析痰湿体质与代谢综合征的相关性。
结果:
痰湿体质理论研究中医传统文献中对痰湿体质的认识经历了相当长的历史演变过程。历代医家对痰湿体质理论的形成与发展作出了重要贡献。痰湿体质是由于津液运化失司,而痰湿凝聚,以粘滞重浊为主要特征的体质状态。痰湿体质形成因素主要包括先天禀赋和后天获得两个方面,先天禀赋又分遗传和胎禀,后天因素包括饮食、脏腑功能、情志、地理与气候环境、劳逸、外感、年龄、妇女妊娠及疾病等因素。其中禀赋遗传是痰湿体质形成的内在因素,后天因素是产生痰湿体质的外界条件。痰湿体质的发病趋势主要包括易患消渴、易患中风、易患眩晕、妇人不孕、鼾眠等,相关疾病的病因、病机、治则治法和方药总结,为现代研究糖尿病、肥胖、高血压、脑血管意外、多囊卵巢综合征等疾病提供了理论依据。因人制宜、标本兼顾原则是痰湿体质调理的基本原则,健脾利湿、化痰泻浊是调节痰湿体质的主要方法。
痰湿体质分子生物学特征研究应用Affymetrix GeneChip Mapping 500K Array芯片检测技术,对6例痰湿体质和6例平和体质基因组DNA检测,结合痰湿体质基因表达谱研究结果发现:痰湿体质与平和体质相比,存在拷贝数变异和差异表达基因单核苷酸多态性特征。共检测出15个CNV,分布在1、5、7、8、9、13、15、16、22号染色体,长度在1kb～100kb之间。初步筛选出5个差异表达基因共6个SNP位点,SNP位点分别为rs4237775、rs174455、rs2303536、rs9967820、rs4149268、rs16873516。进一步对相关基因功能分析显示:痰湿体质相关基因主要具有酶活性、固醇运载体活性、结合蛋白、嗅觉感受器等功能,参与碳水化合物代谢途径、糖异生途径、脂肪酸生物合成途径、胆固醇代谢过程、脂肪酸氧化作用、棕色脂肪细胞分化、细胞葡萄糖调节平衡作用、体温调节作用、蛋白水解、G蛋白偶联受体蛋白信号途径等生物学过程。研究结果体现了痰湿体质者具有代谢紊乱的总体特征,在分子水平上对痰湿体质特征进行了初步探索。
痰湿体质与代谢综合征具有相关性3000例人群痰湿体质与代谢综合征的双变量相关分析显示:肯德尔等级相关系数=0.123(P<0.001),斯皮尔曼等级相关系数=0.124(P<0.001),说明痰湿体质与代谢综合征的发生有相关关系,且代谢综合征的发生与痰湿体质的程度正相关。病例对照研究方法对9种体质类型进行多元Logistic回归分析显示:在P<0.05水平,最终进入回归方程的相关体质因素有3个,分别是平和质、痰湿质、湿热质,其中痰湿质、湿热质为代谢综合征发生的危险因素,根据回归系数比较可见痰湿质在代谢综合征的发病中相对重要。以代谢综合征基本危险因素和生化标志物为指标对痰湿体质和平和体质的比较研究显示:痰湿体质体重指数(BMI)显著高于平和体质者(P<0.001),腰围显著高于平和体质者(P<0.001);痰湿体质总胆固醇(TC)显著高于平和体质者(P<0.001),甘油三酯(TG)显著高于平和体质者(P<0.001),低密度脂蛋白胆固醇(LDL-C)显著高于平和质者(P<0.01),高密度脂蛋白胆固醇(HDL-C)显著低于平和体质者(P<0.001),揭示部分痰湿体质存在血脂代谢紊乱,主要表现TG、TC、LDL-C处于临界高值;痰湿体质血压水平显著高于平和体质(P<0.05);痰湿体质者空腹血糖水平、空腹胰岛素水平显著高于平和体质者(P<0.05),部分痰湿质存在糖代谢障碍,主要表现为正常血糖时痰湿体质者空腹血糖均数高于平和质者,并有部分痰湿体质者存在空腹血糖损害、高胰岛素血症及胰岛素抵抗;痰湿体质血尿酸(UA)水平显著高于平和体质者(P<0.001),其中部分痰湿体质者UA水平高于正常值,提示痰湿体质存在嘌呤代谢障碍;痰湿体质脂联素水平显著低于平和体质(P<0.001)。初步说明痰湿体质与代谢综合征发病在一定程度上具有相关性。
结论:
研究认为,痰湿体质是受禀赋遗传、后天获得等多因素影响,而形成的具有一定形体结构、生理功能与心理特征的,表现为对相关疾病具有易罹性的一种体质类型。
分子生物学研究表明痰湿体质是多基因参与形成的一种体质状态,痰湿体质与平和体质相比在SNP和CNV上具有特征,相关基因功能分析显示痰湿体质者总体表现为代谢紊乱。SNP基因分型芯片检测技术及SNP芯片与表达谱结合的研究手段在技术方法上具有一定的创新性。
痰湿体质与代谢综合征具有相关性,是代谢综合征最主要的危险体质因素。痰湿体质者具有肥胖、糖代谢、脂代谢和嘌呤代谢紊乱等代谢特征,与平和体质相比,其多项代谢综合征危险因素和危险标志物均有显著差异,是代谢综合征高危人群之一,痰湿体质的判定有利于代谢综合征高危人群的筛选。代谢综合征等代谢性疾病是痰湿体质者主要发病趋势,从痰湿体质的角度出发是研究代谢综合征病理机制、预防和治疗的途径之一。
本研究为阐释中医“治未病”思想和“异病同治”原则进行了一次探索,是对通过体质研究进行疾病防治的尝试。
Objective:To excavate the related theories of phlegm-dampness constitution from Traditional Chinese Medicine theory,summarize contemporary research achievement and expatiate the theories of phlegm-dampness constitution and its application.to explore the characteristics of single nucleotide polymorphisms(SNP)and copy number variation(CNV)of phlegm-dampness constitution,analyze the related gene function,expatiate the molecule mechanism. Develop correlation researchs between phlegm-dampness constitution and metabolic syndrome(MS) to prove the morbility proneness of phlegm-dampness constitution and provide theory basis to prevent these diseases early.
Methods:By the hods of the traditional literature research and the contemporary literature analysis,we discuss the correlative theories of phlegm-dampness constitution from origin to development , from connotation to extension. by summarizing the clinical experience,this article discusses the application of phlegm-dampness constitution theory in preventing and curing disease. This subject uses Affymetrix GeneChip Mapping 500K Array to explore the characteristics of SNP and CNV of phlegm-dampness constitution. Utilize clinical epidemiology and medical statistics to analyze the correlation between phlegm-dampness constitution and MS.
Results:It has been a long time for the traditional literature of TCM to the cognition of phlegm-dampness constitution. From the research,we consider that phlegm-dampness constitution is one of the common types of constitution which is affected by congenital heredity and acquired predisposition,and it can form certain body structure,physiological function and mental profile , and be prone to suffering from correlative diseases. Phlegm-dampness constitution can be regulated,which is the effective measure to prevent and cure correlative diseases.
Examining the genome DNA of peripheral blood cells of six phlegm-dampness constitution and six normal constitution by using Affymetrix GeneChip Mapping 500K Array,15 CNVs and 6 SNPs with significant differences were identified between the phlegm-dampness constitution and the normal constitution. Further biological theme analysis on the genes identified between two constitution groups demonstrate that they are involve in enzyme activity, sterol transporter activity,olfactory receptor and binding protein, participate the biology process of the carbohydrate metabolism, gluconeogenesis, glycolytic pathway, lipid metabolism, cholesterol metabolic process,brown fat cell differentiation and proteolysis.
We have proved a correlation between phlegm-dampness constitution and MS through the study of 3000 individuals via bivariate correlate.We detected the phlegm-dampness constitution is the most dangerous constitution factor of MS by the case-control study. Persons of phlegm-dampness constitution have higher level on body mass index(BMI), waistline(WC), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose(FBG), Fasting insulin(Fins),uric acid(UA) and have lower level on high-density lipoprotein cholesterol(HDL-C), adiponectin compared with those of normal constitution. There was significant difference between two groups(P<0.05).
Conclusions : Theory study indicate: Phlegm-dampness constitution is a biased constitution state whose characteristic is stagnation of phlegm and dampness due to the dysfunction of transportation. Its formation is related to congenital heredity and acquired predisposition. The developing tendency of phlegm-dampness constitution is the stagnation of phlegm and dampness,and phlegm complicated with stasis,that lead to vertigo,apoplexy,thoracic obstruction and diabetes gradually. Invigorating the spleen,disinhibiting dampness,resolving phlegm,promoting the flow of qi,exercise and diet cure are the main methods for regulating phlegm-dampness constitution.
Phlegm-dampness constitution is one of the types of constitution which is related to polygene,and has its unique SNP and CNV profile comparing with normal constitution persons. function of genes identified manifests that the gene characteristic of phlegm-dampness constitution is related to metabolism disorder.
There is a relationship between phlegm-dampness constitutions and MS. Our results revealed persons of phlegm-dampness constitution have dysfuctions in lipid metabolism, glycometabolism and purine metabolism, they are high risk group of MS. Research on phlegm-dampness constitution is a way to investigate pathomechanism, prophylaxis and treatment of MS.
方法:采用传统文献梳理与现代文献分析的方法,进行中医痰湿体质理论研究。应用Affymetrix公司GeneChip Mapping 500K Array检测技术,比较分析痰湿体质与平和体质者单核苷酸多态性和拷贝数变异差异,在分子水平探索痰湿体质的特征。采用临床流行病学、医学统计学方法分析痰湿体质与代谢综合征的相关性。
结果:
痰湿体质理论研究中医传统文献中对痰湿体质的认识经历了相当长的历史演变过程。历代医家对痰湿体质理论的形成与发展作出了重要贡献。痰湿体质是由于津液运化失司,而痰湿凝聚,以粘滞重浊为主要特征的体质状态。痰湿体质形成因素主要包括先天禀赋和后天获得两个方面,先天禀赋又分遗传和胎禀,后天因素包括饮食、脏腑功能、情志、地理与气候环境、劳逸、外感、年龄、妇女妊娠及疾病等因素。其中禀赋遗传是痰湿体质形成的内在因素,后天因素是产生痰湿体质的外界条件。痰湿体质的发病趋势主要包括易患消渴、易患中风、易患眩晕、妇人不孕、鼾眠等,相关疾病的病因、病机、治则治法和方药总结,为现代研究糖尿病、肥胖、高血压、脑血管意外、多囊卵巢综合征等疾病提供了理论依据。因人制宜、标本兼顾原则是痰湿体质调理的基本原则,健脾利湿、化痰泻浊是调节痰湿体质的主要方法。
痰湿体质分子生物学特征研究应用Affymetrix GeneChip Mapping 500K Array芯片检测技术,对6例痰湿体质和6例平和体质基因组DNA检测,结合痰湿体质基因表达谱研究结果发现:痰湿体质与平和体质相比,存在拷贝数变异和差异表达基因单核苷酸多态性特征。共检测出15个CNV,分布在1、5、7、8、9、13、15、16、22号染色体,长度在1kb～100kb之间。初步筛选出5个差异表达基因共6个SNP位点,SNP位点分别为rs4237775、rs174455、rs2303536、rs9967820、rs4149268、rs16873516。进一步对相关基因功能分析显示:痰湿体质相关基因主要具有酶活性、固醇运载体活性、结合蛋白、嗅觉感受器等功能,参与碳水化合物代谢途径、糖异生途径、脂肪酸生物合成途径、胆固醇代谢过程、脂肪酸氧化作用、棕色脂肪细胞分化、细胞葡萄糖调节平衡作用、体温调节作用、蛋白水解、G蛋白偶联受体蛋白信号途径等生物学过程。研究结果体现了痰湿体质者具有代谢紊乱的总体特征,在分子水平上对痰湿体质特征进行了初步探索。
痰湿体质与代谢综合征具有相关性3000例人群痰湿体质与代谢综合征的双变量相关分析显示:肯德尔等级相关系数=0.123(P<0.001),斯皮尔曼等级相关系数=0.124(P<0.001),说明痰湿体质与代谢综合征的发生有相关关系,且代谢综合征的发生与痰湿体质的程度正相关。病例对照研究方法对9种体质类型进行多元Logistic回归分析显示:在P<0.05水平,最终进入回归方程的相关体质因素有3个,分别是平和质、痰湿质、湿热质,其中痰湿质、湿热质为代谢综合征发生的危险因素,根据回归系数比较可见痰湿质在代谢综合征的发病中相对重要。以代谢综合征基本危险因素和生化标志物为指标对痰湿体质和平和体质的比较研究显示:痰湿体质体重指数(BMI)显著高于平和体质者(P<0.001),腰围显著高于平和体质者(P<0.001);痰湿体质总胆固醇(TC)显著高于平和体质者(P<0.001),甘油三酯(TG)显著高于平和体质者(P<0.001),低密度脂蛋白胆固醇(LDL-C)显著高于平和质者(P<0.01),高密度脂蛋白胆固醇(HDL-C)显著低于平和体质者(P<0.001),揭示部分痰湿体质存在血脂代谢紊乱,主要表现TG、TC、LDL-C处于临界高值;痰湿体质血压水平显著高于平和体质(P<0.05);痰湿体质者空腹血糖水平、空腹胰岛素水平显著高于平和体质者(P<0.05),部分痰湿质存在糖代谢障碍,主要表现为正常血糖时痰湿体质者空腹血糖均数高于平和质者,并有部分痰湿体质者存在空腹血糖损害、高胰岛素血症及胰岛素抵抗;痰湿体质血尿酸(UA)水平显著高于平和体质者(P<0.001),其中部分痰湿体质者UA水平高于正常值,提示痰湿体质存在嘌呤代谢障碍;痰湿体质脂联素水平显著低于平和体质(P<0.001)。初步说明痰湿体质与代谢综合征发病在一定程度上具有相关性。
结论:
研究认为,痰湿体质是受禀赋遗传、后天获得等多因素影响,而形成的具有一定形体结构、生理功能与心理特征的,表现为对相关疾病具有易罹性的一种体质类型。
分子生物学研究表明痰湿体质是多基因参与形成的一种体质状态,痰湿体质与平和体质相比在SNP和CNV上具有特征,相关基因功能分析显示痰湿体质者总体表现为代谢紊乱。SNP基因分型芯片检测技术及SNP芯片与表达谱结合的研究手段在技术方法上具有一定的创新性。
痰湿体质与代谢综合征具有相关性,是代谢综合征最主要的危险体质因素。痰湿体质者具有肥胖、糖代谢、脂代谢和嘌呤代谢紊乱等代谢特征,与平和体质相比,其多项代谢综合征危险因素和危险标志物均有显著差异,是代谢综合征高危人群之一,痰湿体质的判定有利于代谢综合征高危人群的筛选。代谢综合征等代谢性疾病是痰湿体质者主要发病趋势,从痰湿体质的角度出发是研究代谢综合征病理机制、预防和治疗的途径之一。
本研究为阐释中医“治未病”思想和“异病同治”原则进行了一次探索,是对通过体质研究进行疾病防治的尝试。
Objective:To excavate the related theories of phlegm-dampness constitution from Traditional Chinese Medicine theory,summarize contemporary research achievement and expatiate the theories of phlegm-dampness constitution and its application.to explore the characteristics of single nucleotide polymorphisms(SNP)and copy number variation(CNV)of phlegm-dampness constitution,analyze the related gene function,expatiate the molecule mechanism. Develop correlation researchs between phlegm-dampness constitution and metabolic syndrome(MS) to prove the morbility proneness of phlegm-dampness constitution and provide theory basis to prevent these diseases early.
Methods:By the hods of the traditional literature research and the contemporary literature analysis,we discuss the correlative theories of phlegm-dampness constitution from origin to development , from connotation to extension. by summarizing the clinical experience,this article discusses the application of phlegm-dampness constitution theory in preventing and curing disease. This subject uses Affymetrix GeneChip Mapping 500K Array to explore the characteristics of SNP and CNV of phlegm-dampness constitution. Utilize clinical epidemiology and medical statistics to analyze the correlation between phlegm-dampness constitution and MS.
Results:It has been a long time for the traditional literature of TCM to the cognition of phlegm-dampness constitution. From the research,we consider that phlegm-dampness constitution is one of the common types of constitution which is affected by congenital heredity and acquired predisposition,and it can form certain body structure,physiological function and mental profile , and be prone to suffering from correlative diseases. Phlegm-dampness constitution can be regulated,which is the effective measure to prevent and cure correlative diseases.
Examining the genome DNA of peripheral blood cells of six phlegm-dampness constitution and six normal constitution by using Affymetrix GeneChip Mapping 500K Array,15 CNVs and 6 SNPs with significant differences were identified between the phlegm-dampness constitution and the normal constitution. Further biological theme analysis on the genes identified between two constitution groups demonstrate that they are involve in enzyme activity, sterol transporter activity,olfactory receptor and binding protein, participate the biology process of the carbohydrate metabolism, gluconeogenesis, glycolytic pathway, lipid metabolism, cholesterol metabolic process,brown fat cell differentiation and proteolysis.
We have proved a correlation between phlegm-dampness constitution and MS through the study of 3000 individuals via bivariate correlate.We detected the phlegm-dampness constitution is the most dangerous constitution factor of MS by the case-control study. Persons of phlegm-dampness constitution have higher level on body mass index(BMI), waistline(WC), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose(FBG), Fasting insulin(Fins),uric acid(UA) and have lower level on high-density lipoprotein cholesterol(HDL-C), adiponectin compared with those of normal constitution. There was significant difference between two groups(P<0.05).
Conclusions : Theory study indicate: Phlegm-dampness constitution is a biased constitution state whose characteristic is stagnation of phlegm and dampness due to the dysfunction of transportation. Its formation is related to congenital heredity and acquired predisposition. The developing tendency of phlegm-dampness constitution is the stagnation of phlegm and dampness,and phlegm complicated with stasis,that lead to vertigo,apoplexy,thoracic obstruction and diabetes gradually. Invigorating the spleen,disinhibiting dampness,resolving phlegm,promoting the flow of qi,exercise and diet cure are the main methods for regulating phlegm-dampness constitution.
Phlegm-dampness constitution is one of the types of constitution which is related to polygene,and has its unique SNP and CNV profile comparing with normal constitution persons. function of genes identified manifests that the gene characteristic of phlegm-dampness constitution is related to metabolism disorder.
There is a relationship between phlegm-dampness constitutions and MS. Our results revealed persons of phlegm-dampness constitution have dysfuctions in lipid metabolism, glycometabolism and purine metabolism, they are high risk group of MS. Research on phlegm-dampness constitution is a way to investigate pathomechanism, prophylaxis and treatment of MS.
引文
[1]王琦.中医体质学.北京:中国医药科技出版社,1995:55.
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