中老年人群高尿酸血症及常见体质类型的代谢组学特征
|
摘要
背景：
高尿酸血症(HUA)是血中尿酸(UA)水平升高超出正常范围的一种疾病状态。近年来大量流行病学研究提示：高尿酸血症可能是肾脏疾病的独立危险因素。除了能引起肾脏疾病外,与痛风、冠心病、心肌梗死、脑梗死等疾病的发生发展密切相关,并且已经成为代谢综合征的一部分。随着经济水平增长及人们生活方式的改变,高尿酸血症患病率有不断增高趋势。2011年研究表明：北京社区老人中高尿酸血症患病率为9.8%,其中老年女性患病率为9.9%、男性为9.6%,女性稍高于男性。2012年在中老年人群健康体检中发现：高尿酸血症的患病率达到了23.45%,且男性患病人数多于女性,男女高尿酸血症患病人数之比接近2：1。近年国外研究报道：中老年人高尿酸血症患病率达到了50%。中老年人群高尿酸血症已经成为普遍关注的健康问题。
体质现象是人类生命活动中的一种重要表现形式。然而在中医理论指导下对各种体质类型的生理病理特点、疾病的发生发展变化进行研究的体质学说称为中医体质学说,其目的是指导疾病预防和治疗。有研究对350名城市社区中老年人群中医体质调查,体质结果依次为：平和体质占49.4%、气虚体质占14.0%、痰湿体质占8.6%、阳虚体质占8.0%、阴虚体质占6.9%、血瘀体质占6.6%、气郁体质占5.1%、特禀体质占2.9%及湿热体质占1.1%。又有对广东60-80岁中老年人群进行中医体质辨识,结果显示：体质依次排列为气虚体质占57.71%、痰湿体质占38.32%、阳虚体质：阴虚体质占23.60%、血瘀体质占22.20%、平和体质占1.64%、气郁体质占1.17%、湿热体质占1.17%及特禀体质占0.96%。众多学者对高尿酸血症进行了中医体质辨识,有报道对高尿酸血症患者123例进行了体质分析,结果显示：气虚痰湿体质104例、湿热体质10例、血瘀体质9例。有研究对痛风患者26例进行中医体质分析,结果显示：痰湿体质17例、平和体质4例、平和体质兼痰湿体质3例、阳虚体质1例、气虚体质1例,从而揭示了痛风病发生发展与中医体质有一定相互关系。有学者对新疆地区高尿酸血症患者进行中医体质研究发现：常见的中医体质类型是痰湿体质、湿热体质和血瘀体质。有学者研究报道：痛风患者中以中老年男性及绝经期后的女性为多见,并且多数患者具有形体肥胖、嗜食肥甘等痰湿体质特征,从而得出体质与痛风有相关联的结论。
代谢组学(metabonomics)是近年来迅速发展起来的一门新兴科学,其目的在于系统研究小分子代谢产物。Metabonomics技术是应用现代分析方法对某一生物、细胞、血液或体液在特定的生理时间内对所有相对低分子量的代谢产物进行定性和定量同时进行分析的科学技术。有研究者把高尿酸血症与metabonomics结合起来进行研究,结果发现：高尿酸血症患者存在脂质类代谢异常、糖酵解加剧等现象,这些代谢产物的改变可能与高尿酸血症的发生发展变化、病程及预后转归有关系。尿酸与血糖的代谢密切相关。尿酸与三酰甘油虽然不属于同一物质的代谢途径,但是三酰甘油降解生成游离脂肪酸再酯化进入其他组织的过程,会增加三磷酸腺苷(ATP)的利用率,加速ATP的分解,使尿酸生成增加。
因此,对中老年人群高尿酸血症及常见中医体质类型进行代谢组学研究,是深入研究中老年人群高尿酸血症、中老年人群常见中医体质类型发病机制及二者相互关系的重要途径,该代谢组特征的揭示,有助于加深人们对于中老年人群高尿酸血症、中医偏颇体质中老年人群功能紊乱及内环境变化的认识,从而拓宽中医健康调养的干预思路,提高辨体调养的针对性。
目的：
1.探讨社区中老年人群高尿酸血症患病率及其与性别、年龄的关系；2.探讨社区中老年人群中医体质分布、正常血尿酸社区中老年人群的中医体质分布、社区中老年人群高尿酸血症患者中医体质分布以及体质与性别、年龄的关系；3.采用液相色谱-质谱联用技术探讨中老年人群高尿酸血症及其中老年人群常见中医体质类型的代谢组学特征,寻找代谢标志物,为进一步研究高尿酸血症发病机制及其体质易感性奠定基础。
方法：
1.调查研究：2012年5月在广州市芳村区茶窖社区采用流行病学调查方法对55岁及以上中老年常住居民进行高尿酸血症筛查、健康状况普查；采用2009年中华中医药学会正式颁布的《中医体质量表》采集中医体质辨识相关信息,同时进行抽血检查。中医体质辨识信息采集由经过统一培训的调查人员进行现场调查。由专职人员对原始资料进行检查,剔除填写资料不全的中医体质量表。用EpiData3.1软件建立数据库,由专职人员进行调查表信息的录入；采取不同人员进行二次录入的方法。中医体质评分由《中医健康管理软件》内嵌的体质评分系统自动计算,研究人员依据体质评分结果判别体质类型。统计软件采用SPSS17.0进行统计学分析与处理。--般性资料采用描述性分析、推断性分析,计数资料计算构成比及率,组间比较采用χ2检验(或确切概率法)。计量资料计算x±s,组件比较采用t检验(非正态分布或方差不齐,采用秩和检验,检验水平α=0.05)。
2.代谢组学研究：根据研究目标制定目标人群筛选的纳入与排除标准,依据标准从社区调查数据库中筛选目标人群,调取原始数据,并从血标本库中调取相应的血清标本进行代谢组学检测。目标人群根据调查结果分为4组：①中老年人群高尿酸血症组；②中老年人群正常血尿酸组；③中老年人群气虚体质组；④中老年人群平和体质组。其中中老年人群高尿酸血症组与中老年人群正常组比较；中老年人群气虚体质组与中老年人群平和体质组比较；各组之间无统计学差异,具有可比性。各组采集血液标本后,分离血清均保存于-80℃冰箱,检测时,置4。C冰箱过夜冻融后,于100μ1血清中加入甲醇400μL,涡旋5min,4℃离心(15min,13000rpm/min),取上清液,将上清液置于96孔板中,进样分析。采用色相液谱-质谱联用技术进行代谢组学分析。对PLS-DA分析得到的VIP(Variable Importance in the Projection)值大于1的化合物采用t检验进行组间比较,筛查出组间具有显著性差异(P<0.05)的化合物。通过检索分子式检索数据库(http://www.genome.jp/kegg/ligand.html和http://redpoll.pharmacy.ualberta.ca/～aguo/www_hmdb_ca/HMDB/)鉴定出潜在的生物标志物。
结果：
1.调查研究：社区常住成年居民共824名参加流行病学调查的健康状况普查研究,其中55岁及以上中老年人共463名被纳入高尿酸血症筛查、健康状况普查研究。年龄在55-113岁之间,平均年龄69.46±7.747岁,其中男性142名、占30.67%,女性321名、占69.33%。正常血尿酸者228名,其中男性79名、占34.65%,女性149名、占65.35%。高尿酸血症者235名,其中男性63名、占26.80%,女性172名、占73.20%。高尿酸血症患病率总体为50.76%,女性为53.58%、男性为44.37%；按年龄组55-64岁、65-74岁及75岁及以上分层,患病率分别是53.40%、48.51%及52.80%；按年龄组55-69岁及70岁及以上分层,患病率分别是50%及51.54%。中医体质类型方面：463名调查人群中276人有中医体质辨识结果,中医体质类型依次为平和质142人(30.67%)、气虚质48人(10.37%)、阳虚质42人(9.07%)、痰湿质22人(4.75%)、气郁质9人(1.94%)、阴虚质9人(1.94%)、特禀质3人(0.65%)及湿热质1人(0.22%)；228名正常血尿酸者中144人有中医体质辨识结果,中医体质类型依次为平和质74人(32.46%)、气虚质25人(10.97%)、阳虚质24人(10.53%)、痰湿质10人(4.39%)、阴虚质5人(2.20%)、气郁质4人(1.75%)、特禀质1人(0.44%)及湿热质1人(0.44%)：235名高尿酸血症患者中132人有中医体质辨识结果,中医体质类型依次为平和质68人(28.94%)、气虚质23人(9.79%)、阳虚质18人(7.66%)、痰湿质12人(5.11%)、气郁质5人(2.13%)、阴虚质4人(1.70%)及特禀质2人(0.85%)。常见中医体质类型方面：正常血尿酸者中最常见中医体质类型依次为平和质、气虚质及阳虚质；高尿酸血症人群中最常见中医体质类型依次为平和质、气虚质及阳虚质。
2.代谢组学研究：共检测血清样本80例,其中血尿酸正常者40例(平和体质20例,气虚体质20例)；高尿酸血症者40例(平和体质20例,气虚体质20例)。通过组间对比筛选出高尿酸血症潜在标志物15个,主要涉及脂类代谢、糖代谢及能量代谢等代谢途径；中老年人群气虚体质潜在标志物15个,主要涉及脂类代谢、糖代谢、能量代谢、蛋白代谢及类固醇代谢等代谢途径。中老年人群高尿酸血症与中老年人群气虚体质共同潜在标志物3个,主要涉及脂类代谢及糖酵解代谢两个途径。
结论：
1.高尿酸血症是社区中老年人群常见病,患病率为50.76%,其中女性是53.58%、男性为是44.37%。
2.平和质、气虚质及阳虚质是社区中老年人群的常见体质类型；高尿酸血症中老年人群与正常血尿酸中老年人群的常见体质类型均为平和质、气虚质及阳虚质。
3.中老年人群高尿酸血症代谢特征表现为脂类代谢、糖代谢及能量代谢等代谢途径的异常；中老年人群气虚体质代谢特征表现为脂类代谢、糖代谢、能量代谢、蛋白质代谢及类固醇代谢等代谢途径的异常。中老年人群高尿酸血症及中老年人群气虚体质共同代谢特征表现为脂类代谢途径及糖酵解代谢途径的异常。
Background
Hyperuricemia is a disease characterized by significantly higher uric acid (UA) level in the blood of patients. Recent epidemiological studies have suggested that Hyperuricemia may be an independent risk factor for kidney disease. Beyond inducing kidney disease, Hyperuricemia is closely related with the occurrence and growth of gout, coronary heart disease, myocardial infarction and cerebral infarction, and has become a significant factor of metabolic syndrome. With the development of economy and the change of living style, the prevalence of senile Hyperuricemia shows an increasing tendency. A2011study showed that the prevalence rate of Hyperuricemia was9.8%in Beijing community elderly, and the prevalence rate in females (9.9%) is significantly higher than that in males (9.6%). However, Health-Examination results of middle-aged and elderly people in2012showed that prevalence rate of Hyperuricemia was23.45%, and the prevalence rate in males is higher than that in females by nearly2-to-1. Recent foreign studies reported that prevalence rate of Hyperuricemia in the elderly has reached50%. Above all, Hyperuricemia in the elderly population has become a major public health problem.
The phenomenon of constitution is an important manifestation of life activity in human being and it is closely related to disease and health. Traditional Chinese Medical (TCM) Constitution guided by traditional Chinese medicine theory is used to study various physical characteristics, physiological and pathological features, as well as analyze disease state, the nature of the lesion and development trends. Many scholars have studied the TCM constitution of patients with Hyperuricemia. Results of one study on123cases of patients with Hyperuricemia constitutional analysis showed that 104cases were qi deficiency and phlegm constitution,10cases were damp-heat constitution, and9cases were blood stasis constitution. Accounting for TCM constitution type,26patients with gout were classified. Results showed17cases with physical phlegm constitution,4cases with mildly constitution,3cases with mildly and dampness constitution,1case with yang deficiency,1case with Qi deficiency, revealing that the incidence of gout has the certain relations with TCM constitution. Studies on the TCM constitution of patients with Hyperuricemia in Xinjiang have found that the common types are phlegm-dampness constitution, damp-heat constitution and blood stasis. Studies have reported that patients with gout are mainly middle-aged men and post-menopausal women, and most patients are characterized by Phlegm-dampness constitution manifesting as body fat and food addiction, therefore the conclusion can be made that constitution is associated with gout.
Metabolomics is a rapidly developing, aiming at small molecule metabolites science. Being an essential component of systematic biology, metabolomics is a post genomic technology aimed at seeking to provide a comprehensive profile of all the metabolites present in a biological sample in a particular physiological period, such as organism, cells, blood or body fluids. Results of some studies on combining Hyperuricemia and metabolomics showed that abnormal metabolism of glucose and lipoid were found in patients with Hyperuricemia (HUA), these metabolites change may be associated with the pathogenesis, progress, and prognosis of HUA. Uric acid is closely related to the metabolic levels of blood glucose. Although the material metabolism paths of triglyceride (TG) are not the same to those of Uric acid (UA), the degradation process of triglyceride generated free fatty acid and esterification into other organizations will increase the utilization rate of adenosine triphosphate (ATP), accelerate ATP decomposition and increased production of uric acid.
Therefore, combining metabolomics and TCM constitution of middle-aged and aged patients with Hyperuricemia is an important method to study prevalence and pathogenesis of Hyperuricemia in middle-aged and aged population, and it will provide theoretical basis for clinical treatment. Research on this subject has broad prospects and practical significance.
Objective
The objectives of this study:①To explore the incidence of Hyperuricemia in middle-aged and aged population and the impact of gender, age;②To explore TCM constitution of middle-aged and aged patients with Hyperuricemia and the impact of gender, age;③To analyze the metabolite composition of samples and find out metabolic markers of common TCM constitution from middle-aged and aged patients with Hyperuricemia using liquid chromatography-mass spectrometry technology, it will provide theoretical basis for the study of pathogenesis.
Methods
In the clinical studies, a cross-section epidemiological investigation was carried out on community residents in Guangzhou. Correct differentiation of constitutional pattern referring to the constitution of TCM criterion of2009, and drew blood for analysis. All the subjects were interviewed with a questionnaire by specially trained professional person in a standardized way. Calculate sample size, and the guideline of choosing and excluding case was established. The mildly constitution is considered normal, while other8kinds of constitution were unhealthy constitution. All original data were examined by professionals, and unqualified questionnaire should be eliminated. Epidata3.1software was used to build data record system; and the raw data was placed into the system by two operators. Statistical analysis was accomplished with SPSS17.0soft package. According to the research needs, we carried out descriptive analysis of the distribution feature, and then analyzed the characteristic variables such as age, gender and so on; Chi-square test were applied when more than one objective indicators discussed in various differences between groups were significant; We intend to adopt unconditioned Logistic regression analysis to explore the internal distribution and characteristics, while we didn't do it as the incomplete data collection. In experimental aspect, patients were grouped according to the results of investigation:①Hyperuricemia group;②Control group;③Hyperuricemia with mildly constitution group;④Hyperuricemia with qi-insufficiency constitution group. Hyperuricemia group and Hyperuricemia with qi-insufficiency constitution group have no significant differences compared with control group and Hyperuricemia with mildly constitution group, respectively. Collect, classify and preserve the serum at-80degrees and make a clear sign of everyone's information. Freeze thawing at4degrees overnight.400μL methanol is added into the serum (per100μL), then the solutions should be vortexes for4minutes and centrifuge at4degrees (15min,13000rpm/min), thus supernatant is obtained and put into in96-well plates for chemical analysis. HPLC/MS were used to do the metabolomics experiment, compounds with significant difference between groups(P<0.05) were screened out according to VIP (Variable Importance in the Projection) value(≧1) got from PLS-DA analysis combined with t test. Then identify potential biomarkers according to formula searchable database,(http://www.genome.jp/kegg/ligand.html and http://redpoll. pharmacy.ualberta. ca/～aguo/www_hmdb_ca/HMDB/)
Results
In the clinical research, the study involved463participants, including235patients with Hyperuricemia(172females and63males) and228controls; The prevalence of Hyperuricemia is50.76%and significantly higher in women(53.58%) than in men (44.37%); The prevalence of Hyperuricemia in the age groups of55-64years,65-74years and75-84years were53.40%,48.51%and52.80%, respectively; And in the age groups of55-69years,70-84years were50%and51.54%, respectively. People with mildly constitution account for30.67%among elderly people; subjects with normouricemia (32.46%) were significantly higher than those with Hyperuricemia (28.81%). Common TCM Constitutions among elderly people with Hyperuricemia were mildly constitution, qi-insufficiency constitution and yang-insufficiency constitution, accounting for28.81%,9.7%and7.63%, respectively. In experimental aspect, the metabolic markers of Hyperuricemia included: acylglycerol phospholipid; hemolytic lecithin; lecithin; triglycerides; diglyceride; acyldehydrogenase; Uridine-5'-diphosphoglucose; acetyl CoA; pentosan; stearoyl-CoA; dehydrocholesterol; homocysteine; phosphatidylserine; dihydroxyacetone phosphate and acyl monoethanolamide. The metabolic markers of Hyperuricemia with qi-insufficiency constitution included:acyl glycine, cardiolipin, glycerine phosphatide, glycosphingolipids, phospholipids, inositol phospholipids, ceramide, lysophosphatide acid, sulfate, DHT dihydroxy acetone phosphate, lysolecithin, pure ammonia acyl alanine, leukotriene, aspartic acid, etc. Common metabolic markers of Hyperuricemia and Hyperuricemia with qi-insufficiency constitution included:Glycerine phosphatide, hemolytic lecithin and dihydroxyacetone phosphate.
Conclusion
In the clinical research, the prevalence of Hyperuricemia is significantly higher in women than in men among middle aged and elderly people; when stratified by age, different stratified sampling method obtained different results. If we classified subject participants into three categories (55-64years,65-74years and75-84years), prevalence of Hyperuricemia were descend by the increase of age; however, when we classified subject participants into two categories, prevalence of Hyperuricemia increased with age. The proportion of participants with Hyperuricemia is higher than those with normouricemia in the middle-aged and old women, while the proportion of participants with Hyperuricemia is lower than those with normouricemia in the middle-aged and old men. For the participants with mildly constitution, the proportion of participants with Hyperuricemia is higher than those with normouricemia. Sorting by TCM Constitution:mildly constitution>qi-insufficiency constitution>yang-insufficiency.
In the experimental aspect, Middle aged and elderly people with Hyperuricemia differ in several aspects, such as lipid metabolism, glucose metabolism and energy metabolism. And there were difference in lipid, protein, sugar, energy and steroid metabolism for patients with qi-insufficiency constitution. Lipid and glucose metabolism were common metabolic markers for Hyperuricemia and Hyperuricemia with qi-insufficiency constitution.
There are some shortcuts in this thesis. In the epidemiological cross-sectional investigation, limitations of this study include:small sample size, although it is greater than the minimum requirement; Low repossessions rate of constitution questionnaire, although it is greater than the minimum requirement (71%); inadequate data of middl—aged and elderly men. Therefore, further research on epidemiological cross-sectional investigation is necessary. In the experimental aspect, although we has carried on the statistical analysis of the metabonomics markers content, the accurate molecular structure of these metabolic marker also need to be further studied and confirmed. All in all, the setting up of correlative experiment analysis made good foundation for deeper research work.
高尿酸血症(HUA)是血中尿酸(UA)水平升高超出正常范围的一种疾病状态。近年来大量流行病学研究提示：高尿酸血症可能是肾脏疾病的独立危险因素。除了能引起肾脏疾病外,与痛风、冠心病、心肌梗死、脑梗死等疾病的发生发展密切相关,并且已经成为代谢综合征的一部分。随着经济水平增长及人们生活方式的改变,高尿酸血症患病率有不断增高趋势。2011年研究表明：北京社区老人中高尿酸血症患病率为9.8%,其中老年女性患病率为9.9%、男性为9.6%,女性稍高于男性。2012年在中老年人群健康体检中发现：高尿酸血症的患病率达到了23.45%,且男性患病人数多于女性,男女高尿酸血症患病人数之比接近2：1。近年国外研究报道：中老年人高尿酸血症患病率达到了50%。中老年人群高尿酸血症已经成为普遍关注的健康问题。
体质现象是人类生命活动中的一种重要表现形式。然而在中医理论指导下对各种体质类型的生理病理特点、疾病的发生发展变化进行研究的体质学说称为中医体质学说,其目的是指导疾病预防和治疗。有研究对350名城市社区中老年人群中医体质调查,体质结果依次为：平和体质占49.4%、气虚体质占14.0%、痰湿体质占8.6%、阳虚体质占8.0%、阴虚体质占6.9%、血瘀体质占6.6%、气郁体质占5.1%、特禀体质占2.9%及湿热体质占1.1%。又有对广东60-80岁中老年人群进行中医体质辨识,结果显示：体质依次排列为气虚体质占57.71%、痰湿体质占38.32%、阳虚体质：阴虚体质占23.60%、血瘀体质占22.20%、平和体质占1.64%、气郁体质占1.17%、湿热体质占1.17%及特禀体质占0.96%。众多学者对高尿酸血症进行了中医体质辨识,有报道对高尿酸血症患者123例进行了体质分析,结果显示：气虚痰湿体质104例、湿热体质10例、血瘀体质9例。有研究对痛风患者26例进行中医体质分析,结果显示：痰湿体质17例、平和体质4例、平和体质兼痰湿体质3例、阳虚体质1例、气虚体质1例,从而揭示了痛风病发生发展与中医体质有一定相互关系。有学者对新疆地区高尿酸血症患者进行中医体质研究发现：常见的中医体质类型是痰湿体质、湿热体质和血瘀体质。有学者研究报道：痛风患者中以中老年男性及绝经期后的女性为多见,并且多数患者具有形体肥胖、嗜食肥甘等痰湿体质特征,从而得出体质与痛风有相关联的结论。
代谢组学(metabonomics)是近年来迅速发展起来的一门新兴科学,其目的在于系统研究小分子代谢产物。Metabonomics技术是应用现代分析方法对某一生物、细胞、血液或体液在特定的生理时间内对所有相对低分子量的代谢产物进行定性和定量同时进行分析的科学技术。有研究者把高尿酸血症与metabonomics结合起来进行研究,结果发现：高尿酸血症患者存在脂质类代谢异常、糖酵解加剧等现象,这些代谢产物的改变可能与高尿酸血症的发生发展变化、病程及预后转归有关系。尿酸与血糖的代谢密切相关。尿酸与三酰甘油虽然不属于同一物质的代谢途径,但是三酰甘油降解生成游离脂肪酸再酯化进入其他组织的过程,会增加三磷酸腺苷(ATP)的利用率,加速ATP的分解,使尿酸生成增加。
因此,对中老年人群高尿酸血症及常见中医体质类型进行代谢组学研究,是深入研究中老年人群高尿酸血症、中老年人群常见中医体质类型发病机制及二者相互关系的重要途径,该代谢组特征的揭示,有助于加深人们对于中老年人群高尿酸血症、中医偏颇体质中老年人群功能紊乱及内环境变化的认识,从而拓宽中医健康调养的干预思路,提高辨体调养的针对性。
目的：
1.探讨社区中老年人群高尿酸血症患病率及其与性别、年龄的关系；2.探讨社区中老年人群中医体质分布、正常血尿酸社区中老年人群的中医体质分布、社区中老年人群高尿酸血症患者中医体质分布以及体质与性别、年龄的关系；3.采用液相色谱-质谱联用技术探讨中老年人群高尿酸血症及其中老年人群常见中医体质类型的代谢组学特征,寻找代谢标志物,为进一步研究高尿酸血症发病机制及其体质易感性奠定基础。
方法：
1.调查研究：2012年5月在广州市芳村区茶窖社区采用流行病学调查方法对55岁及以上中老年常住居民进行高尿酸血症筛查、健康状况普查；采用2009年中华中医药学会正式颁布的《中医体质量表》采集中医体质辨识相关信息,同时进行抽血检查。中医体质辨识信息采集由经过统一培训的调查人员进行现场调查。由专职人员对原始资料进行检查,剔除填写资料不全的中医体质量表。用EpiData3.1软件建立数据库,由专职人员进行调查表信息的录入；采取不同人员进行二次录入的方法。中医体质评分由《中医健康管理软件》内嵌的体质评分系统自动计算,研究人员依据体质评分结果判别体质类型。统计软件采用SPSS17.0进行统计学分析与处理。--般性资料采用描述性分析、推断性分析,计数资料计算构成比及率,组间比较采用χ2检验(或确切概率法)。计量资料计算x±s,组件比较采用t检验(非正态分布或方差不齐,采用秩和检验,检验水平α=0.05)。
2.代谢组学研究：根据研究目标制定目标人群筛选的纳入与排除标准,依据标准从社区调查数据库中筛选目标人群,调取原始数据,并从血标本库中调取相应的血清标本进行代谢组学检测。目标人群根据调查结果分为4组：①中老年人群高尿酸血症组；②中老年人群正常血尿酸组；③中老年人群气虚体质组；④中老年人群平和体质组。其中中老年人群高尿酸血症组与中老年人群正常组比较；中老年人群气虚体质组与中老年人群平和体质组比较；各组之间无统计学差异,具有可比性。各组采集血液标本后,分离血清均保存于-80℃冰箱,检测时,置4。C冰箱过夜冻融后,于100μ1血清中加入甲醇400μL,涡旋5min,4℃离心(15min,13000rpm/min),取上清液,将上清液置于96孔板中,进样分析。采用色相液谱-质谱联用技术进行代谢组学分析。对PLS-DA分析得到的VIP(Variable Importance in the Projection)值大于1的化合物采用t检验进行组间比较,筛查出组间具有显著性差异(P<0.05)的化合物。通过检索分子式检索数据库(http://www.genome.jp/kegg/ligand.html和http://redpoll.pharmacy.ualberta.ca/～aguo/www_hmdb_ca/HMDB/)鉴定出潜在的生物标志物。
结果：
1.调查研究：社区常住成年居民共824名参加流行病学调查的健康状况普查研究,其中55岁及以上中老年人共463名被纳入高尿酸血症筛查、健康状况普查研究。年龄在55-113岁之间,平均年龄69.46±7.747岁,其中男性142名、占30.67%,女性321名、占69.33%。正常血尿酸者228名,其中男性79名、占34.65%,女性149名、占65.35%。高尿酸血症者235名,其中男性63名、占26.80%,女性172名、占73.20%。高尿酸血症患病率总体为50.76%,女性为53.58%、男性为44.37%；按年龄组55-64岁、65-74岁及75岁及以上分层,患病率分别是53.40%、48.51%及52.80%；按年龄组55-69岁及70岁及以上分层,患病率分别是50%及51.54%。中医体质类型方面：463名调查人群中276人有中医体质辨识结果,中医体质类型依次为平和质142人(30.67%)、气虚质48人(10.37%)、阳虚质42人(9.07%)、痰湿质22人(4.75%)、气郁质9人(1.94%)、阴虚质9人(1.94%)、特禀质3人(0.65%)及湿热质1人(0.22%)；228名正常血尿酸者中144人有中医体质辨识结果,中医体质类型依次为平和质74人(32.46%)、气虚质25人(10.97%)、阳虚质24人(10.53%)、痰湿质10人(4.39%)、阴虚质5人(2.20%)、气郁质4人(1.75%)、特禀质1人(0.44%)及湿热质1人(0.44%)：235名高尿酸血症患者中132人有中医体质辨识结果,中医体质类型依次为平和质68人(28.94%)、气虚质23人(9.79%)、阳虚质18人(7.66%)、痰湿质12人(5.11%)、气郁质5人(2.13%)、阴虚质4人(1.70%)及特禀质2人(0.85%)。常见中医体质类型方面：正常血尿酸者中最常见中医体质类型依次为平和质、气虚质及阳虚质；高尿酸血症人群中最常见中医体质类型依次为平和质、气虚质及阳虚质。
2.代谢组学研究：共检测血清样本80例,其中血尿酸正常者40例(平和体质20例,气虚体质20例)；高尿酸血症者40例(平和体质20例,气虚体质20例)。通过组间对比筛选出高尿酸血症潜在标志物15个,主要涉及脂类代谢、糖代谢及能量代谢等代谢途径；中老年人群气虚体质潜在标志物15个,主要涉及脂类代谢、糖代谢、能量代谢、蛋白代谢及类固醇代谢等代谢途径。中老年人群高尿酸血症与中老年人群气虚体质共同潜在标志物3个,主要涉及脂类代谢及糖酵解代谢两个途径。
结论：
1.高尿酸血症是社区中老年人群常见病,患病率为50.76%,其中女性是53.58%、男性为是44.37%。
2.平和质、气虚质及阳虚质是社区中老年人群的常见体质类型；高尿酸血症中老年人群与正常血尿酸中老年人群的常见体质类型均为平和质、气虚质及阳虚质。
3.中老年人群高尿酸血症代谢特征表现为脂类代谢、糖代谢及能量代谢等代谢途径的异常；中老年人群气虚体质代谢特征表现为脂类代谢、糖代谢、能量代谢、蛋白质代谢及类固醇代谢等代谢途径的异常。中老年人群高尿酸血症及中老年人群气虚体质共同代谢特征表现为脂类代谢途径及糖酵解代谢途径的异常。
Background
Hyperuricemia is a disease characterized by significantly higher uric acid (UA) level in the blood of patients. Recent epidemiological studies have suggested that Hyperuricemia may be an independent risk factor for kidney disease. Beyond inducing kidney disease, Hyperuricemia is closely related with the occurrence and growth of gout, coronary heart disease, myocardial infarction and cerebral infarction, and has become a significant factor of metabolic syndrome. With the development of economy and the change of living style, the prevalence of senile Hyperuricemia shows an increasing tendency. A2011study showed that the prevalence rate of Hyperuricemia was9.8%in Beijing community elderly, and the prevalence rate in females (9.9%) is significantly higher than that in males (9.6%). However, Health-Examination results of middle-aged and elderly people in2012showed that prevalence rate of Hyperuricemia was23.45%, and the prevalence rate in males is higher than that in females by nearly2-to-1. Recent foreign studies reported that prevalence rate of Hyperuricemia in the elderly has reached50%. Above all, Hyperuricemia in the elderly population has become a major public health problem.
The phenomenon of constitution is an important manifestation of life activity in human being and it is closely related to disease and health. Traditional Chinese Medical (TCM) Constitution guided by traditional Chinese medicine theory is used to study various physical characteristics, physiological and pathological features, as well as analyze disease state, the nature of the lesion and development trends. Many scholars have studied the TCM constitution of patients with Hyperuricemia. Results of one study on123cases of patients with Hyperuricemia constitutional analysis showed that 104cases were qi deficiency and phlegm constitution,10cases were damp-heat constitution, and9cases were blood stasis constitution. Accounting for TCM constitution type,26patients with gout were classified. Results showed17cases with physical phlegm constitution,4cases with mildly constitution,3cases with mildly and dampness constitution,1case with yang deficiency,1case with Qi deficiency, revealing that the incidence of gout has the certain relations with TCM constitution. Studies on the TCM constitution of patients with Hyperuricemia in Xinjiang have found that the common types are phlegm-dampness constitution, damp-heat constitution and blood stasis. Studies have reported that patients with gout are mainly middle-aged men and post-menopausal women, and most patients are characterized by Phlegm-dampness constitution manifesting as body fat and food addiction, therefore the conclusion can be made that constitution is associated with gout.
Metabolomics is a rapidly developing, aiming at small molecule metabolites science. Being an essential component of systematic biology, metabolomics is a post genomic technology aimed at seeking to provide a comprehensive profile of all the metabolites present in a biological sample in a particular physiological period, such as organism, cells, blood or body fluids. Results of some studies on combining Hyperuricemia and metabolomics showed that abnormal metabolism of glucose and lipoid were found in patients with Hyperuricemia (HUA), these metabolites change may be associated with the pathogenesis, progress, and prognosis of HUA. Uric acid is closely related to the metabolic levels of blood glucose. Although the material metabolism paths of triglyceride (TG) are not the same to those of Uric acid (UA), the degradation process of triglyceride generated free fatty acid and esterification into other organizations will increase the utilization rate of adenosine triphosphate (ATP), accelerate ATP decomposition and increased production of uric acid.
Therefore, combining metabolomics and TCM constitution of middle-aged and aged patients with Hyperuricemia is an important method to study prevalence and pathogenesis of Hyperuricemia in middle-aged and aged population, and it will provide theoretical basis for clinical treatment. Research on this subject has broad prospects and practical significance.
Objective
The objectives of this study:①To explore the incidence of Hyperuricemia in middle-aged and aged population and the impact of gender, age;②To explore TCM constitution of middle-aged and aged patients with Hyperuricemia and the impact of gender, age;③To analyze the metabolite composition of samples and find out metabolic markers of common TCM constitution from middle-aged and aged patients with Hyperuricemia using liquid chromatography-mass spectrometry technology, it will provide theoretical basis for the study of pathogenesis.
Methods
In the clinical studies, a cross-section epidemiological investigation was carried out on community residents in Guangzhou. Correct differentiation of constitutional pattern referring to the constitution of TCM criterion of2009, and drew blood for analysis. All the subjects were interviewed with a questionnaire by specially trained professional person in a standardized way. Calculate sample size, and the guideline of choosing and excluding case was established. The mildly constitution is considered normal, while other8kinds of constitution were unhealthy constitution. All original data were examined by professionals, and unqualified questionnaire should be eliminated. Epidata3.1software was used to build data record system; and the raw data was placed into the system by two operators. Statistical analysis was accomplished with SPSS17.0soft package. According to the research needs, we carried out descriptive analysis of the distribution feature, and then analyzed the characteristic variables such as age, gender and so on; Chi-square test were applied when more than one objective indicators discussed in various differences between groups were significant; We intend to adopt unconditioned Logistic regression analysis to explore the internal distribution and characteristics, while we didn't do it as the incomplete data collection. In experimental aspect, patients were grouped according to the results of investigation:①Hyperuricemia group;②Control group;③Hyperuricemia with mildly constitution group;④Hyperuricemia with qi-insufficiency constitution group. Hyperuricemia group and Hyperuricemia with qi-insufficiency constitution group have no significant differences compared with control group and Hyperuricemia with mildly constitution group, respectively. Collect, classify and preserve the serum at-80degrees and make a clear sign of everyone's information. Freeze thawing at4degrees overnight.400μL methanol is added into the serum (per100μL), then the solutions should be vortexes for4minutes and centrifuge at4degrees (15min,13000rpm/min), thus supernatant is obtained and put into in96-well plates for chemical analysis. HPLC/MS were used to do the metabolomics experiment, compounds with significant difference between groups(P<0.05) were screened out according to VIP (Variable Importance in the Projection) value(≧1) got from PLS-DA analysis combined with t test. Then identify potential biomarkers according to formula searchable database,(http://www.genome.jp/kegg/ligand.html and http://redpoll. pharmacy.ualberta. ca/～aguo/www_hmdb_ca/HMDB/)
Results
In the clinical research, the study involved463participants, including235patients with Hyperuricemia(172females and63males) and228controls; The prevalence of Hyperuricemia is50.76%and significantly higher in women(53.58%) than in men (44.37%); The prevalence of Hyperuricemia in the age groups of55-64years,65-74years and75-84years were53.40%,48.51%and52.80%, respectively; And in the age groups of55-69years,70-84years were50%and51.54%, respectively. People with mildly constitution account for30.67%among elderly people; subjects with normouricemia (32.46%) were significantly higher than those with Hyperuricemia (28.81%). Common TCM Constitutions among elderly people with Hyperuricemia were mildly constitution, qi-insufficiency constitution and yang-insufficiency constitution, accounting for28.81%,9.7%and7.63%, respectively. In experimental aspect, the metabolic markers of Hyperuricemia included: acylglycerol phospholipid; hemolytic lecithin; lecithin; triglycerides; diglyceride; acyldehydrogenase; Uridine-5'-diphosphoglucose; acetyl CoA; pentosan; stearoyl-CoA; dehydrocholesterol; homocysteine; phosphatidylserine; dihydroxyacetone phosphate and acyl monoethanolamide. The metabolic markers of Hyperuricemia with qi-insufficiency constitution included:acyl glycine, cardiolipin, glycerine phosphatide, glycosphingolipids, phospholipids, inositol phospholipids, ceramide, lysophosphatide acid, sulfate, DHT dihydroxy acetone phosphate, lysolecithin, pure ammonia acyl alanine, leukotriene, aspartic acid, etc. Common metabolic markers of Hyperuricemia and Hyperuricemia with qi-insufficiency constitution included:Glycerine phosphatide, hemolytic lecithin and dihydroxyacetone phosphate.
Conclusion
In the clinical research, the prevalence of Hyperuricemia is significantly higher in women than in men among middle aged and elderly people; when stratified by age, different stratified sampling method obtained different results. If we classified subject participants into three categories (55-64years,65-74years and75-84years), prevalence of Hyperuricemia were descend by the increase of age; however, when we classified subject participants into two categories, prevalence of Hyperuricemia increased with age. The proportion of participants with Hyperuricemia is higher than those with normouricemia in the middle-aged and old women, while the proportion of participants with Hyperuricemia is lower than those with normouricemia in the middle-aged and old men. For the participants with mildly constitution, the proportion of participants with Hyperuricemia is higher than those with normouricemia. Sorting by TCM Constitution:mildly constitution>qi-insufficiency constitution>yang-insufficiency.
In the experimental aspect, Middle aged and elderly people with Hyperuricemia differ in several aspects, such as lipid metabolism, glucose metabolism and energy metabolism. And there were difference in lipid, protein, sugar, energy and steroid metabolism for patients with qi-insufficiency constitution. Lipid and glucose metabolism were common metabolic markers for Hyperuricemia and Hyperuricemia with qi-insufficiency constitution.
There are some shortcuts in this thesis. In the epidemiological cross-sectional investigation, limitations of this study include:small sample size, although it is greater than the minimum requirement; Low repossessions rate of constitution questionnaire, although it is greater than the minimum requirement (71%); inadequate data of middl—aged and elderly men. Therefore, further research on epidemiological cross-sectional investigation is necessary. In the experimental aspect, although we has carried on the statistical analysis of the metabonomics markers content, the accurate molecular structure of these metabolic marker also need to be further studied and confirmed. All in all, the setting up of correlative experiment analysis made good foundation for deeper research work.
引文
[1]杨雪静,刘冬梅,董春芳,等.教师中高尿酸血症与代谢综合征危险因素的病例对照研究.中国慢性病预防与控制,2010,18(2)：139-141.
[2]关绍晨,汤哲,方向华,等.北京部分社区老年人高尿酸血症患病相关因素的横断面调查.心肺血管病杂志,2011,30(6)：480-483.
[3]王奎晶,孙丽君,夏楠,等.哈尔滨市老年体检人群高尿酸血症相关因素分析.中外医疗,2012,22：149-150.
[4]Arromdee E, Michet CJ, Crowson CSet al. Epidemiology of gout is the incidence rising?J Rheumatol,2002;29(11):2403-6.
[5]王素平,张卫杰,洪佳璇.杭州市萧山区门诊体检中老年人高尿酸血症患病及相关因素研究.中国初级卫生保健,2008,22(1)：71-73.
[6]黄胜华,连希艳.高尿酸血症及其肾损伤的研究进展.医学研究生学报2010,23(11)：1217-1221.
[7]王琦.中医体质学说研究现状与展望[J].中国中医基础医学杂志,2002,8(2)：6-15.
[8]董建新,王珍,舒成章,等.城市社区中老年人群体质类型分布研究.中国民族民间医药,2010,19(6)：63-64.
[9]陈润东,杨志敏,林媾钊等.中医体质分型6525例调查分析[J].南京中医药大学学报,2009,25(2)：104-106.
[10]潘启焕,张周,覃佰强.高尿酸血症123例的中医体质辨证及疗效分析.中医国医药科学,2011,1(8)：125.
[11]邓棋卫,涂爱国.痛风的辨证调养[J].时珍国医国药,2008,19(6)：1307-1308.
[12]李莉,安冬青,李凯利,等.新疆地区高尿酸血症患者体质类型调查分析.中医临床研究,2012,4(15)：100-103.
[13]李明蕾,吴承玉.痛风病的病症研究思路探讨[J].浙江中医学院学报,2004,28(3)：7-8.
[14]毛煜,袁伯俊.代谢组学的研究现状与展望.中国新药杂志,2007,16(13)：1005-1010.
[15]钟麒,高玉霞,常红.等.男性高尿酸血症患者血浆代谢组学的研究.天津医药.2011,39(8)：695-697.
[16]余俊文,陆锦波,张小娟,等.佛山地区1324例居民血尿酸水平及相关指标分析[J].中国中西医结合肾病杂志,2005,6(7)：401-403.
[17]郑黎强,李觉,余金明,等.冠心病患者尿酸与外周动脉阻塞性疾病的相关性研究[J].中华流行病学杂志,2006,27(2)：161-164.
[18]彭仙娥,赖智双.高尿酸血症与疾病关系的研究进展.中外医疗.2009,(32)：29-30.
[19]刘佳,李玲.高尿酸血症的发病机制与药物治疗研究进展.国际药学研究杂志,2010,37(1)：24-28.
[20]Zhang Yu. Gout[M].Beijing:Technology literature publishing company,2005.
[21]朱君,余俊文.高尿酸血症和痛风的流行病学及其危险因素的研究进展.现代生物医学进展,2008,8(1)：191-195.
[22]Choi H K, Curhan G. Beer, liquor, and wine consumption and serum uric acid level:The third national health and nutrition examination survey[J]. Arthritis Rheum,2004,51: 1023.
[23]Mikuls TR, Saag KG. New insights into gout epidemiology[J]_CurrOpin Rheumatol,2006,18(2):199-20.
[24]Gibson T,Rodgers A, Simmonds H, et al. Beer drinking and its efecon uric acid[J].Br J Rheumatol,1984,23:203-209.
[25]袁智敏,张丽嵩,杨丽芳.广州地区人群高尿酸血症的调查分析[J].营养学报,2004,26(3)：201.
[26]Huang Hy, Appel Lj,Choi MJ, et al.The effects of vitamin C supplementation on senlm concentrations of uric acid:results of a randomized, controlled trial[J]. Arthritis Rheum,2005,52:1843-1847.
[27]Meng BoDa. Professional Athletes and coach's motility trauma and gout[J]. China clinical healing,2004,8(6):1112(In Chinese).
[28]周英.血尿酸浓度变化与高血压关系的探讨[J].中国医师杂志,2004,28(3)：571-576.
[29]薛丽.高尿酸血症与心血管疾病研究进展[J].医学综述,2006,12(2)：90-91.
[30]李宏超,伍沪生.高尿酸血症及痛风与代谢综合征[J].临床内科杂志,2005,22(12)：797-799.
[31]Shen Yi-ping, Jiang Ze-you, Chen Shu-tao. The exploration betweenhyperuricemia and the related disease[J]. Sichuan Medicine,2005,26:1218-1219(In Chinese)
[32]Oyama C, Takahashi T, Oyamada M, et al. Serum uric acid as obesity related indicator in early adolescence[J]. Tohoku J Exp Med,2006,209:257-262
[33]许萍,莫宝庆,刘尧芬,等.南京市中老年人高尿酸血症检出情况及相关因素的分析[J].肠外与肠内营养,2006,13(6)：350-352.
[34]Enomoto A, Niwa T, Kanai Y, et al.Urate transporter and renal hyperuricemia[J]. Rinsho Byori,2003,51(9):892-897.
[35]Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and moleeular analysis of patients with renal hyperuricemia in Japan:influence of URAT1 gone on urinary urate excretion[J]. JAm Soc Nephrol,2004,15(1):164-173
[36]Erdman AR, Mangravte LM,Urban TJ,et al.The human organ-icanion transpoer 3 (OAT3; SLC22A8):genetic variationand functional genomics[J]. Am JPhysiolRenalPhyswl,2006, 290(4):F905-F912.
[37]Hyink DP, Rappopo Jz, Wilson PD, et al. Expression of the uratetransporter/channel is developmentally regulated in human kidneys. AmJ Physiol Renal Physiol,2001,281:875-886.
[38]Ghani AA, Al Waheeb S, A1 Homoud E, et al. Clinical an histopathological spectrumof IgA nephropathy in Kuwait[J]. Ann Saudi Med,2011,31 (2):152-157.
[39]姜雪,许菲菲,章建娜,等.IgA肾病并发高尿酸血症患者5年随访研究[J]中华肾脏病杂志,2011,27(1)：53-54.
[40]Hovind P, Rossing P, Tarnow L, et al. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes:aninception cohort study [J]. Diabetes,2009,58(7):1668-1671.
[41]Zoppini G, Targher G, Chonchol M, et al. Serum uric acid levels and incident chronickiidney disease in patients with type 2 diab etesand preserved kidney function [J].Diabete Care,2012,35 (1):99-104.
[42]邹贵勉,黄江燕,车文体,等.广西城市社区居民高尿酸血症流行病学调查及其与慢性肾脏病的关系[J].中华内分泌代谢杂志,2011,27(7)：561-565.
[43]向月应,眭维国,邹贵勉,等.高尿酸血症肾损害社区流行病学调查及其危险因素分析[J].中华保健医学杂志,2009,11(3)：195-197.
[44]Meier Kriesehe HU, Schold JD, Vanrenterghem Y, et al. Uric acid levels havno significant effect on renalfunctionin adurenal transplant recipients:evidence fromthe symphony study[J]. Clin J Am SocNephrol,2009,4(10):1655-1660.
[45]王丽娟.中医体质学的研究进展.中国民间疗法,2012,20(5)：79-80.
[46]丁宇炜.中医体质学研究进展.云南中医中药杂志,2010,31(2)：71-75.
[47]王迎,金桂兰.中医体质学说研究进展.长春中医药大学学报,2011,27(6)：1067-1068.
[48]任辉.中医体质学说的研究进展.内蒙古中医药,2012,(3)：111-113.
[49]王艳宇,王红霞.中医体质学的研究概况.中国中医药现代远程教育,2011,9(20)：152-153.
[50]李紫慕,常虹,高小明,刘岩.中医体质学理论研究进展.内蒙古中医药,2007,(1)：68-69.
[51]王志如,纪会芳.中医体质学说研究文献探讨.河南中医学院学报,2006,21(123)：79-81.
[52]张云云,张海梅,等.168例缺血性脑卒中患者体质特点研究.上海中医药杂志,2008,42(2)：31-34.
[53]周昭辉,徐志锐,等.浅谈瘀血体质与中风病的防治.光明中医,2009,24(5)：792-794.
[54]项凤梅,邓科穗,刘红宁,等.胆囊息肉患者中医体质分类及相关指标分析[J].南昌大学学报(医学版),2010,50(12)：26-28.
[55]邱丽英,邓科穗,项风梅,等.胆石症患者中医体质与相关指标的关系[J].南昌大学学报(医学版),2010,50(12)：35-37.
[56]夏仲元,王琦,郭琪,等.甲亢和甲减中医体质类型调查分析[J].北京中医药大学学报,2010,33(4)：280-282.
[57]沈乃莹,严征.HLA-DQAI等位基因与急性脑栓塞多种中医体质类型的相关性研究[J].中医杂志,2001,43(4)：237-238.
[58]林谦,陈众木,金法.371例原发性高血压患者的中医体质辨证研究[J].现代中医,2004(3)：17-18.
[59]王志如,纪会芳.中医体质学说研究文献探讨.河南中医学院学报,2006,21(123)：79-81.
[60]王琦.王琦医学论文集,北京：中国大百科全书出版社,1994：98.
[61]王琦,叶加农.肥胖人痰湿体质的血液流变学和甲皱微循环研究[J].中国中医基础医学杂志,1995,1(1)：52-54.
[62]许建阳,刘志诚,宋开源,等.择时电针不同体质大鼠创伤痛诱导的肾上腺Fos／Jun蛋白表达的比较研究[J].时间医学,1999,4(1)：20-21.
[63]李紫慕,常虹,高小明.中医体质学理论研究进展.内蒙古中医药,2007,(1)：68-69.
[64]刘长灵,过建春,荀运浩.中医体质学说现代研究进展.浙江中医药大学学报,2009,33(1)：138-139.
[65]Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancerprogression. Nature,2009,457:910-914.
[66]Nicholson JK, Lindon JC, Holmes E'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica,1999,29:1181-1189.
[67]毛煜,袁伯俊.代谢组学的研究现状与展望.中国新药杂志,2007,16(13)：1005-1010.
[68]蒋怀周,鲍远程.代谢组学应用于中医药研究的思考.中医药学报,2010,38(4)：63-67.
[69]林景超,李后开,周明眉,等.代谢组学、药物代谢组学与中医药现代化.中国医学科学院学报,2007,29(6)：818-822.
[70]王斯婷李晓娜,王皎,等.代谢组学及其分析技术.药物分析杂志,2010,30(9)：1792-1798.
[71]Nicholson JK, Lindon JC, Holmes E.'Metabonomics'.-understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectmscopie data. Xenobiotica,1999,29(11):1181.
[72]王斯婷,李晓娜,王皎,等.代谢组学及其分析技术.药物分析杂志,2010,30(9)：1792-1798.
[73]Fiehn 0, Kopka J, Dormann P, et al. Metabolite profiling for plant functional genomics. Nat Biotechnol 2000;18(11):1157.
[74]高嘉元,摇严玉澄.代谢组学技术在肾脏病研究中的应用.中国中西医结合肾病杂志,2011,12(5)：466-470.
[75]Brindle JT.Antti H, Holmes E. et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1-NMR based metabonomics[J]. Nat Med,2002,8 (12):1439-1444.
[76]Amberg A. Stammberger I. Kurz M. et al. Metabonomics investigation of ochratoxin A (OTA) induced nephrotoxicity[J]. Toxicol Applied Pharmacol,2004,197(3):309-310.
[77]汪尔康.生命分析化学[M].北京：科学出版社,2006：887-888.
[78]赵维薇,许文涛,王奠,等.代谢组学研究技术及其应用.生物技术通报,2011,12：57-63.
[79]Taylor J, King RD, Ahmann T,et al. Application of metabonomics to plant genotype discrimination using statistics and machine learning. Bioinformaties,2002,18:241.
[80]范群丽,陈晓虎.代谢组学技术在中医证候研究中的应用概况.江苏中医药,2010,42(7)：79-81.
[81]Wang M, Lamers RJ, Korthout HA,van Nesselrooij JH, Witkamp RF, et al. Metabolomics in the context of systems biology:bridging traditional Chinese medicine and molecular pharmacology.Phytother Res,2005,19:173-182.
[82]Verpoorte R, Choi YH, Kim HK Ethnopharmacology and systems biology:a perfect holistic match. J Ethnopharmacol,2005,100:53-56.
[83]李英帅.应用代谢组学技术进行中医药研究探讨.安徽中医学院学报,2008,27(6)：1-5.
[84]朱嘉,方祝元.代谢组学与中医“证”的相关性.现代中西医结合杂志,2009,18(8)：938-941.
[85]Schnackenberg LK, Beger RD. Monitoring the health to disease continuum with global metabolic profiling and systems biology. Pharmacogenomics,2006,7(7):1077.
[86]邓鑫.代谢组学在中医药研究中的应用.云南中医中药杂志,2010,31(9)：73-75.
[87]邓鑫.代谢组学在中医药研究中的应用.云南中医中药杂药,2011,22(7)：1755-1758.
[88]赵维薇,许文涛,王奠,等.代谢组学研究技术及其应用.生物技术通报,2011,12：57-63.
[89]Dalluge JJ, Smith S, Sanchez Riera F.et al. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry, J Chromatogr A.2004,1043:3-7.
[90]刘萍,王平,陈刚,等.应用代谢组学探讨中医药复杂理论体系的研究思路和方法.中华中医药杂志,2011,26(5)：993-998.
[91]袁卓琚.应用代谢组学探讨中医体质与证候关系问题.中国中医药信息杂志,2012,19(6)：5-6.
[92]林景超,李后开,周明眉.代谢组学、药物代谢组学与中医药现代化.中国医学科学院学报,2007,29(6)：818-822.
[93]杨雪静,刘冬梅,董春芳,等.教师中高尿酸血症与代谢综合征危险因素的病例对照研究.中国慢性病预防与控制,2010,18(2)：139-141.
[94]吴巧风,颜贤忠,唐勇,等.代谢组学在我国中医药领域的应用.四川中医,2008,26(31)：7-9.
[95]Viazz. F, Parod D, Leoncin G, et al. Serum uric acid and target organ damage in primary hypertension[J]. Hypertension,2005,45(5):991-996.
[96]安代志,郭长江.代谢组学与营养学研究[J].生理科学进展,2007,38(3)：277-279.
[97]陈靖刚,于俊青,舒勤,张磊.老年人高尿酸血症与代谢综合征相关因素研究进展.河北医药,2012,34(3)：432-434.
[98]陈灏珠,林果.实用内科学.北京：人民卫生出版社,2009,第13版：2766.
[99]关绍晨,汤哲,方向华,等.北京部分社区老年人高尿酸血症患病相关因素的横断面调查.心肺血管病杂志,2011,30(6)：480-483.
[100]王琦.中医体质分类与判定[M].北京：中国中医药出版社,2009,1-5
[101]张立晶,胡大一,杨进刚,等.有心血管疾病危险因素人群中高尿酸血症的发生率及其相关因素.首都医科大学学报,2005,26(2)：125-127.
[102]王琴,马晓曼.老年高尿酸血症175例相关因素分析.中国社区医师,2012,14(32)：26-27.
[103]李莉,安冬青,李凯利.新疆地区高尿酸血症患者体质类型调查分析.中医临床研究,2012,4(15)：100-103.
[104]赵维薇,许文涛,王奠,等.代谢组学研究技术及其应用.生物技术通报,2011；12：57-63.
[105]张德超,王素英,王翠英.转化胆固醇的微生物在食品中的应用研究[J].中国食品学报,1999(11)：85-126.
[106]Lehmann B, Genehr T, Knuschke P. UVB-induced conversion of 7-dehydrocholes terol to 1A,25-d ihyd roxyvitam in D3 in an invitro human skin equivalent model [J].J Invest D ermatol,2001,117 (5):1179-1185.
[107]Antonio V, Anpuchchelv Ira, Bjorn C, et al.7-Dehyd rocholesterolenhances ultraviolet A-induced oxidative stress in keratinocytes:Roles of NADPH oxidase, mitochondria, and lipid rafts [J]. Free Radical BioMed,2006,41:1704-1718.
[108]钟麒,高玉霞,常红,等.男性高尿酸血症患者血浆代谢组学的研究[J].天津医药,2011,39(8)：695-697.
[109]马文峰,马志刚,王万山,等.基于液相色谱—质谱技术的高尿酸血症血浆代谢组学研究.重庆医学,2013,42(2)：176-179.
[110]武尚文,曹彤,李伟,等.血脂异常与慢性肾脏疾病进展的关系.山东医药,2010,50(17)：64-65.
[111]张原力,游凯,方圻,等.脂餐后血清甘油三酯代谢异常作为冠心病独立危险因素的探讨.中华心血管病杂志,1998,26(2)：89-93.
[112]周林,张远慧.三磷酸肌醇和甘油二醋在冠心病、高血压发病中的作用.心血管病学进展,1993,14(5)：293-296.
[113]彭恭,杜雅兰,徐式孟,等.http://www.cnki.com.cn/Article/CJFDTotal-SMKX201111012.htm,2011.11,1.
[114]张惠敏,郑守曾.气虚体质的研究进展.北京中医药大学学报,2004,27(1)：14-16.
[115]张莹.抗心磷脂抗体所致自然流产的中西医结合治疗进展.中国中医药信息杂志,2005,12(12)：102-103.
[116]Nishizulka Y. Turnover of inositol phospholipids and signal transduction. Science,1984,225:1365.
[117]佟万成,罗慰慈.溶血磷脂酸代谢途径及在炎症中的作用.国外医学呼叫系统分册,1996,16(2)：81-83.
[118]孙九丽,林慧珍,苟萍.鞘脂代谢及其相关疾病研究进展.生物技术,2011,21(5)：94-96.
[119]董强,吴云剑.双氢睾酮在前列腺癌生长及预后中的研究进展.西部医学,2008,20(6)：1135-1140.
[2]关绍晨,汤哲,方向华,等.北京部分社区老年人高尿酸血症患病相关因素的横断面调查.心肺血管病杂志,2011,30(6)：480-483.
[3]王奎晶,孙丽君,夏楠,等.哈尔滨市老年体检人群高尿酸血症相关因素分析.中外医疗,2012,22：149-150.
[4]Arromdee E, Michet CJ, Crowson CSet al. Epidemiology of gout is the incidence rising?J Rheumatol,2002;29(11):2403-6.
[5]王素平,张卫杰,洪佳璇.杭州市萧山区门诊体检中老年人高尿酸血症患病及相关因素研究.中国初级卫生保健,2008,22(1)：71-73.
[6]黄胜华,连希艳.高尿酸血症及其肾损伤的研究进展.医学研究生学报2010,23(11)：1217-1221.
[7]王琦.中医体质学说研究现状与展望[J].中国中医基础医学杂志,2002,8(2)：6-15.
[8]董建新,王珍,舒成章,等.城市社区中老年人群体质类型分布研究.中国民族民间医药,2010,19(6)：63-64.
[9]陈润东,杨志敏,林媾钊等.中医体质分型6525例调查分析[J].南京中医药大学学报,2009,25(2)：104-106.
[10]潘启焕,张周,覃佰强.高尿酸血症123例的中医体质辨证及疗效分析.中医国医药科学,2011,1(8)：125.
[11]邓棋卫,涂爱国.痛风的辨证调养[J].时珍国医国药,2008,19(6)：1307-1308.
[12]李莉,安冬青,李凯利,等.新疆地区高尿酸血症患者体质类型调查分析.中医临床研究,2012,4(15)：100-103.
[13]李明蕾,吴承玉.痛风病的病症研究思路探讨[J].浙江中医学院学报,2004,28(3)：7-8.
[14]毛煜,袁伯俊.代谢组学的研究现状与展望.中国新药杂志,2007,16(13)：1005-1010.
[15]钟麒,高玉霞,常红.等.男性高尿酸血症患者血浆代谢组学的研究.天津医药.2011,39(8)：695-697.
[16]余俊文,陆锦波,张小娟,等.佛山地区1324例居民血尿酸水平及相关指标分析[J].中国中西医结合肾病杂志,2005,6(7)：401-403.
[17]郑黎强,李觉,余金明,等.冠心病患者尿酸与外周动脉阻塞性疾病的相关性研究[J].中华流行病学杂志,2006,27(2)：161-164.
[18]彭仙娥,赖智双.高尿酸血症与疾病关系的研究进展.中外医疗.2009,(32)：29-30.
[19]刘佳,李玲.高尿酸血症的发病机制与药物治疗研究进展.国际药学研究杂志,2010,37(1)：24-28.
[20]Zhang Yu. Gout[M].Beijing:Technology literature publishing company,2005.
[21]朱君,余俊文.高尿酸血症和痛风的流行病学及其危险因素的研究进展.现代生物医学进展,2008,8(1)：191-195.
[22]Choi H K, Curhan G. Beer, liquor, and wine consumption and serum uric acid level:The third national health and nutrition examination survey[J]. Arthritis Rheum,2004,51: 1023.
[23]Mikuls TR, Saag KG. New insights into gout epidemiology[J]_CurrOpin Rheumatol,2006,18(2):199-20.
[24]Gibson T,Rodgers A, Simmonds H, et al. Beer drinking and its efecon uric acid[J].Br J Rheumatol,1984,23:203-209.
[25]袁智敏,张丽嵩,杨丽芳.广州地区人群高尿酸血症的调查分析[J].营养学报,2004,26(3)：201.
[26]Huang Hy, Appel Lj,Choi MJ, et al.The effects of vitamin C supplementation on senlm concentrations of uric acid:results of a randomized, controlled trial[J]. Arthritis Rheum,2005,52:1843-1847.
[27]Meng BoDa. Professional Athletes and coach's motility trauma and gout[J]. China clinical healing,2004,8(6):1112(In Chinese).
[28]周英.血尿酸浓度变化与高血压关系的探讨[J].中国医师杂志,2004,28(3)：571-576.
[29]薛丽.高尿酸血症与心血管疾病研究进展[J].医学综述,2006,12(2)：90-91.
[30]李宏超,伍沪生.高尿酸血症及痛风与代谢综合征[J].临床内科杂志,2005,22(12)：797-799.
[31]Shen Yi-ping, Jiang Ze-you, Chen Shu-tao. The exploration betweenhyperuricemia and the related disease[J]. Sichuan Medicine,2005,26:1218-1219(In Chinese)
[32]Oyama C, Takahashi T, Oyamada M, et al. Serum uric acid as obesity related indicator in early adolescence[J]. Tohoku J Exp Med,2006,209:257-262
[33]许萍,莫宝庆,刘尧芬,等.南京市中老年人高尿酸血症检出情况及相关因素的分析[J].肠外与肠内营养,2006,13(6)：350-352.
[34]Enomoto A, Niwa T, Kanai Y, et al.Urate transporter and renal hyperuricemia[J]. Rinsho Byori,2003,51(9):892-897.
[35]Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and moleeular analysis of patients with renal hyperuricemia in Japan:influence of URAT1 gone on urinary urate excretion[J]. JAm Soc Nephrol,2004,15(1):164-173
[36]Erdman AR, Mangravte LM,Urban TJ,et al.The human organ-icanion transpoer 3 (OAT3; SLC22A8):genetic variationand functional genomics[J]. Am JPhysiolRenalPhyswl,2006, 290(4):F905-F912.
[37]Hyink DP, Rappopo Jz, Wilson PD, et al. Expression of the uratetransporter/channel is developmentally regulated in human kidneys. AmJ Physiol Renal Physiol,2001,281:875-886.
[38]Ghani AA, Al Waheeb S, A1 Homoud E, et al. Clinical an histopathological spectrumof IgA nephropathy in Kuwait[J]. Ann Saudi Med,2011,31 (2):152-157.
[39]姜雪,许菲菲,章建娜,等.IgA肾病并发高尿酸血症患者5年随访研究[J]中华肾脏病杂志,2011,27(1)：53-54.
[40]Hovind P, Rossing P, Tarnow L, et al. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes:aninception cohort study [J]. Diabetes,2009,58(7):1668-1671.
[41]Zoppini G, Targher G, Chonchol M, et al. Serum uric acid levels and incident chronickiidney disease in patients with type 2 diab etesand preserved kidney function [J].Diabete Care,2012,35 (1):99-104.
[42]邹贵勉,黄江燕,车文体,等.广西城市社区居民高尿酸血症流行病学调查及其与慢性肾脏病的关系[J].中华内分泌代谢杂志,2011,27(7)：561-565.
[43]向月应,眭维国,邹贵勉,等.高尿酸血症肾损害社区流行病学调查及其危险因素分析[J].中华保健医学杂志,2009,11(3)：195-197.
[44]Meier Kriesehe HU, Schold JD, Vanrenterghem Y, et al. Uric acid levels havno significant effect on renalfunctionin adurenal transplant recipients:evidence fromthe symphony study[J]. Clin J Am SocNephrol,2009,4(10):1655-1660.
[45]王丽娟.中医体质学的研究进展.中国民间疗法,2012,20(5)：79-80.
[46]丁宇炜.中医体质学研究进展.云南中医中药杂志,2010,31(2)：71-75.
[47]王迎,金桂兰.中医体质学说研究进展.长春中医药大学学报,2011,27(6)：1067-1068.
[48]任辉.中医体质学说的研究进展.内蒙古中医药,2012,(3)：111-113.
[49]王艳宇,王红霞.中医体质学的研究概况.中国中医药现代远程教育,2011,9(20)：152-153.
[50]李紫慕,常虹,高小明,刘岩.中医体质学理论研究进展.内蒙古中医药,2007,(1)：68-69.
[51]王志如,纪会芳.中医体质学说研究文献探讨.河南中医学院学报,2006,21(123)：79-81.
[52]张云云,张海梅,等.168例缺血性脑卒中患者体质特点研究.上海中医药杂志,2008,42(2)：31-34.
[53]周昭辉,徐志锐,等.浅谈瘀血体质与中风病的防治.光明中医,2009,24(5)：792-794.
[54]项凤梅,邓科穗,刘红宁,等.胆囊息肉患者中医体质分类及相关指标分析[J].南昌大学学报(医学版),2010,50(12)：26-28.
[55]邱丽英,邓科穗,项风梅,等.胆石症患者中医体质与相关指标的关系[J].南昌大学学报(医学版),2010,50(12)：35-37.
[56]夏仲元,王琦,郭琪,等.甲亢和甲减中医体质类型调查分析[J].北京中医药大学学报,2010,33(4)：280-282.
[57]沈乃莹,严征.HLA-DQAI等位基因与急性脑栓塞多种中医体质类型的相关性研究[J].中医杂志,2001,43(4)：237-238.
[58]林谦,陈众木,金法.371例原发性高血压患者的中医体质辨证研究[J].现代中医,2004(3)：17-18.
[59]王志如,纪会芳.中医体质学说研究文献探讨.河南中医学院学报,2006,21(123)：79-81.
[60]王琦.王琦医学论文集,北京：中国大百科全书出版社,1994：98.
[61]王琦,叶加农.肥胖人痰湿体质的血液流变学和甲皱微循环研究[J].中国中医基础医学杂志,1995,1(1)：52-54.
[62]许建阳,刘志诚,宋开源,等.择时电针不同体质大鼠创伤痛诱导的肾上腺Fos／Jun蛋白表达的比较研究[J].时间医学,1999,4(1)：20-21.
[63]李紫慕,常虹,高小明.中医体质学理论研究进展.内蒙古中医药,2007,(1)：68-69.
[64]刘长灵,过建春,荀运浩.中医体质学说现代研究进展.浙江中医药大学学报,2009,33(1)：138-139.
[65]Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancerprogression. Nature,2009,457:910-914.
[66]Nicholson JK, Lindon JC, Holmes E'Metabonomics':understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica,1999,29:1181-1189.
[67]毛煜,袁伯俊.代谢组学的研究现状与展望.中国新药杂志,2007,16(13)：1005-1010.
[68]蒋怀周,鲍远程.代谢组学应用于中医药研究的思考.中医药学报,2010,38(4)：63-67.
[69]林景超,李后开,周明眉,等.代谢组学、药物代谢组学与中医药现代化.中国医学科学院学报,2007,29(6)：818-822.
[70]王斯婷李晓娜,王皎,等.代谢组学及其分析技术.药物分析杂志,2010,30(9)：1792-1798.
[71]Nicholson JK, Lindon JC, Holmes E.'Metabonomics'.-understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectmscopie data. Xenobiotica,1999,29(11):1181.
[72]王斯婷,李晓娜,王皎,等.代谢组学及其分析技术.药物分析杂志,2010,30(9)：1792-1798.
[73]Fiehn 0, Kopka J, Dormann P, et al. Metabolite profiling for plant functional genomics. Nat Biotechnol 2000;18(11):1157.
[74]高嘉元,摇严玉澄.代谢组学技术在肾脏病研究中的应用.中国中西医结合肾病杂志,2011,12(5)：466-470.
[75]Brindle JT.Antti H, Holmes E. et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1-NMR based metabonomics[J]. Nat Med,2002,8 (12):1439-1444.
[76]Amberg A. Stammberger I. Kurz M. et al. Metabonomics investigation of ochratoxin A (OTA) induced nephrotoxicity[J]. Toxicol Applied Pharmacol,2004,197(3):309-310.
[77]汪尔康.生命分析化学[M].北京：科学出版社,2006：887-888.
[78]赵维薇,许文涛,王奠,等.代谢组学研究技术及其应用.生物技术通报,2011,12：57-63.
[79]Taylor J, King RD, Ahmann T,et al. Application of metabonomics to plant genotype discrimination using statistics and machine learning. Bioinformaties,2002,18:241.
[80]范群丽,陈晓虎.代谢组学技术在中医证候研究中的应用概况.江苏中医药,2010,42(7)：79-81.
[81]Wang M, Lamers RJ, Korthout HA,van Nesselrooij JH, Witkamp RF, et al. Metabolomics in the context of systems biology:bridging traditional Chinese medicine and molecular pharmacology.Phytother Res,2005,19:173-182.
[82]Verpoorte R, Choi YH, Kim HK Ethnopharmacology and systems biology:a perfect holistic match. J Ethnopharmacol,2005,100:53-56.
[83]李英帅.应用代谢组学技术进行中医药研究探讨.安徽中医学院学报,2008,27(6)：1-5.
[84]朱嘉,方祝元.代谢组学与中医“证”的相关性.现代中西医结合杂志,2009,18(8)：938-941.
[85]Schnackenberg LK, Beger RD. Monitoring the health to disease continuum with global metabolic profiling and systems biology. Pharmacogenomics,2006,7(7):1077.
[86]邓鑫.代谢组学在中医药研究中的应用.云南中医中药杂志,2010,31(9)：73-75.
[87]邓鑫.代谢组学在中医药研究中的应用.云南中医中药杂药,2011,22(7)：1755-1758.
[88]赵维薇,许文涛,王奠,等.代谢组学研究技术及其应用.生物技术通报,2011,12：57-63.
[89]Dalluge JJ, Smith S, Sanchez Riera F.et al. Potential of fermentation profiling via rapid measurement of amino acid metabolism by liquid chromatography-tandem mass spectrometry, J Chromatogr A.2004,1043:3-7.
[90]刘萍,王平,陈刚,等.应用代谢组学探讨中医药复杂理论体系的研究思路和方法.中华中医药杂志,2011,26(5)：993-998.
[91]袁卓琚.应用代谢组学探讨中医体质与证候关系问题.中国中医药信息杂志,2012,19(6)：5-6.
[92]林景超,李后开,周明眉.代谢组学、药物代谢组学与中医药现代化.中国医学科学院学报,2007,29(6)：818-822.
[93]杨雪静,刘冬梅,董春芳,等.教师中高尿酸血症与代谢综合征危险因素的病例对照研究.中国慢性病预防与控制,2010,18(2)：139-141.
[94]吴巧风,颜贤忠,唐勇,等.代谢组学在我国中医药领域的应用.四川中医,2008,26(31)：7-9.
[95]Viazz. F, Parod D, Leoncin G, et al. Serum uric acid and target organ damage in primary hypertension[J]. Hypertension,2005,45(5):991-996.
[96]安代志,郭长江.代谢组学与营养学研究[J].生理科学进展,2007,38(3)：277-279.
[97]陈靖刚,于俊青,舒勤,张磊.老年人高尿酸血症与代谢综合征相关因素研究进展.河北医药,2012,34(3)：432-434.
[98]陈灏珠,林果.实用内科学.北京：人民卫生出版社,2009,第13版：2766.
[99]关绍晨,汤哲,方向华,等.北京部分社区老年人高尿酸血症患病相关因素的横断面调查.心肺血管病杂志,2011,30(6)：480-483.
[100]王琦.中医体质分类与判定[M].北京：中国中医药出版社,2009,1-5
[101]张立晶,胡大一,杨进刚,等.有心血管疾病危险因素人群中高尿酸血症的发生率及其相关因素.首都医科大学学报,2005,26(2)：125-127.
[102]王琴,马晓曼.老年高尿酸血症175例相关因素分析.中国社区医师,2012,14(32)：26-27.
[103]李莉,安冬青,李凯利.新疆地区高尿酸血症患者体质类型调查分析.中医临床研究,2012,4(15)：100-103.
[104]赵维薇,许文涛,王奠,等.代谢组学研究技术及其应用.生物技术通报,2011；12：57-63.
[105]张德超,王素英,王翠英.转化胆固醇的微生物在食品中的应用研究[J].中国食品学报,1999(11)：85-126.
[106]Lehmann B, Genehr T, Knuschke P. UVB-induced conversion of 7-dehydrocholes terol to 1A,25-d ihyd roxyvitam in D3 in an invitro human skin equivalent model [J].J Invest D ermatol,2001,117 (5):1179-1185.
[107]Antonio V, Anpuchchelv Ira, Bjorn C, et al.7-Dehyd rocholesterolenhances ultraviolet A-induced oxidative stress in keratinocytes:Roles of NADPH oxidase, mitochondria, and lipid rafts [J]. Free Radical BioMed,2006,41:1704-1718.
[108]钟麒,高玉霞,常红,等.男性高尿酸血症患者血浆代谢组学的研究[J].天津医药,2011,39(8)：695-697.
[109]马文峰,马志刚,王万山,等.基于液相色谱—质谱技术的高尿酸血症血浆代谢组学研究.重庆医学,2013,42(2)：176-179.
[110]武尚文,曹彤,李伟,等.血脂异常与慢性肾脏疾病进展的关系.山东医药,2010,50(17)：64-65.
[111]张原力,游凯,方圻,等.脂餐后血清甘油三酯代谢异常作为冠心病独立危险因素的探讨.中华心血管病杂志,1998,26(2)：89-93.
[112]周林,张远慧.三磷酸肌醇和甘油二醋在冠心病、高血压发病中的作用.心血管病学进展,1993,14(5)：293-296.
[113]彭恭,杜雅兰,徐式孟,等.http://www.cnki.com.cn/Article/CJFDTotal-SMKX201111012.htm,2011.11,1.
[114]张惠敏,郑守曾.气虚体质的研究进展.北京中医药大学学报,2004,27(1)：14-16.
[115]张莹.抗心磷脂抗体所致自然流产的中西医结合治疗进展.中国中医药信息杂志,2005,12(12)：102-103.
[116]Nishizulka Y. Turnover of inositol phospholipids and signal transduction. Science,1984,225:1365.
[117]佟万成,罗慰慈.溶血磷脂酸代谢途径及在炎症中的作用.国外医学呼叫系统分册,1996,16(2)：81-83.
[118]孙九丽,林慧珍,苟萍.鞘脂代谢及其相关疾病研究进展.生物技术,2011,21(5)：94-96.
[119]董强,吴云剑.双氢睾酮在前列腺癌生长及预后中的研究进展.西部医学,2008,20(6)：1135-1140.