HO-1基因启动子微卫星多态与广东汉族湿热证易感性的相关性研究
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摘要
岭南地处亚热带,濒临南海,地势低洼,又有南岭山脉的屏障作用,形成了独特的地理环境。岭南地区所处纬度较低,是我国较接近赤道的地带,日照多,太阳辐射量大,气候炎热湿润多雨,各地年平均温度在20.4-23.1℃之间,年降雨量大多在1500-2000毫米之间,是全国著名的多雨区。四季划分不明显,夏长冬暖,且一天之中高温延续时间也较长,平均温度较高,致使岭南人酿成阳热体质。广州及珠江三角洲地区年平均相对湿度为78%,3-8月份平均湿度可达到85%。这种炎热湿润气候超过机体调节限度极易形成湿热病邪。且广东地区人们勤泳浴,喜爱鱼虾螺蚝等多湿阴柔之品,加上贪饮生冷冻物,影响人的脾胃运化功能,湿困脾胃而酿成湿热体质。岭南地区由于地理环境、气候因素以及人们的饮食生活习惯、人群体质等导致了湿热证的多发。
体质是人群中的个体在遗传基础上和缓慢的环境因素作用下,在其生长发育过程中所形成的形态、结构、功能、代谢等方面相对稳定的特定躯体素质与心理素质的综合体。它既受先天遗传因素的影响,又受后天环境因素的影响。中医理论认为,体质是证候产生的重要基础,个体体质的特殊性,往往决定着他对某种致病因子的易感性及其所产生病变类型的倾向性。在某种程度上,体质因素决定着疾病的发生、发展和预后,决定证候的类型、转化和转归。每一个人体质的个体特点,都是以遗传因素为基础,在后天生长条件的影响下,经过自然、社会、境遇、饮食等诸多因素的影响和变迁,逐渐发展起来的。由遗传背景所决定的体质差异是维持个体体质特征相对稳定的重要条件。人类基因组序列中的变异是基因组的基本特征之一,而正是这种基因的多态性,即基因组序列的差异构成了不同个体与群体对疾病的易感性、对药物与环境因子不同反应的遗传学基础。它的出现是人类进化和适应环境的必然结果。同时它在人群中的多样性成为不同个体对疾病易感性不同的内因基础。
广东地区气候炎热、高温多雨,因而形成了高温高湿(湿热)的气候特征,机体在这种高温高湿的环境下可发生热应激反应(heat stress response)。血红素加氧酶-1(heme oxygenase-1, HO-1)是一种在进化过程中高度保守的应激蛋白,对维持机体的自身稳定性起重要作用。其主要功能是提高细胞对应激因素的耐受,使细胞维持正常的生理功能,增加细胞对致死性刺激的防御和适应能力。HO-1催化氧化剂血红素的降解,生成胆绿素、一氧化碳、和游离铁。HO-1是一个保护因子,具有抗炎、抗氧化、抗增殖效应。
人HO-1基因启动子区GT双核苷酸重复序列长度多态性影响个体对肺部疾病、心脑血管疾病、肿瘤等多种疾病的易感性。不同长度(GT)n重复序列携带者在机体受到内外界刺激、损伤后发生的反应不同,从而影响机体的适应能力、体质的形成以及对诸多疾病的易感性、耐受性,影响机体对热应激的反应,对高温高湿的适应能力和对湿热证的易感性。血红素加氧酶-1(HO-1)基因启动子微卫星多态性既反映了遗传因素,同时与环境因素密切相关。因此,我们研究了血红素加氧酶-1基因启动子微卫星多态性与广东汉族人湿热证易感性的关系。血清总抗氧化能力(TAOC)测定能显示机体抗氧化防御能力,丙二醛(MDA)可以反映过氧化反应进行的程度。
目的：HO-1基因启动子微卫星多态性与广东汉族人湿热证易感性、地理环境、氧化应激的关系；研究湿热证与氧化应激反应的关系。
方法：参考平和体质、湿热体质判别标准,在志愿者知情同意的情况下收集无阳性病变,无血缘关系的汉族志愿者。
纳入标准：对年龄在18周岁以上(以30-40岁为主),在广东省生活的广东籍汉族家庭成员进行健康调查,受试者的父母籍贯均为广东籍；在广东省居住小于五年的中国非广东籍(主要为北方各省份)汉族人群；受试者的父母均为非广东籍：近一年体检无阳性器质性病变；自愿且能够参加该项目,所有志愿者均需签订知情同意书。
排除标准：非广东籍(主要为北方各省份)汉族人在广东省居住长于五年的人群；年龄18周岁以下；除中国汉族以外的其他民族；志愿者的父母籍贯一方为广东籍；患有呼吸、消化、心脑血管、泌尿、神经、生殖等系统疾病；处于发热期(包括感冒)；心、肝、肺、肾、血脂、血糖等常规实验室检查异常；孕妇、哺乳期妇女；未获得知情同意者。
湿热体质的判定标准参照《中医体质分类与判定》标准,2002年《中药新药临床研究指导原则(试行)》及广州中医药大学脾胃研究所相关标准,制定如下：
主要表现：苔黄、苔腻或厚浊,脉滑数。次要表现：面垢油光,易生痤疮,口苦而粘；渴而少饮：肢体困重；脘闷腹胀；胸闷；大便粘滞不爽；小便黄短。
具备1个主要表现+3个(或以上)次要表现；2个主要表现+2个(或以上)次要表现,即可判定为湿热体质。
对照组选择标准参照《中医体质分类与判定》平和质判别标准：面色、肤色润泽,头发稠密有光泽,目光有神、精力充沛、胃纳佳、睡眠安、二便调、体态适中、平素少病、舌色淡红,苔薄白,脉和缓有力。
分为A、B、C、D组,A组为广东籍湿热体质组,20例；B组为非广东籍湿热体质组,20例；C组为广东籍平和体质组,15例；D组为非广东籍平和体质组15例。A组、B组为湿热体质组,共40例,C组、D组为对照组(平和体质组),共30例；A组、C组为广东籍组,共35人,B组、D组为非广东籍组,共35人。各组性别、年龄无差异,具有可比性。
调查地点选择广东省广州市；调查时间选择在的春分至秋分期间(5-9月份)。
符合纳入标准的各组志愿者空腹静脉采血,采血时间在春分至秋分期间(5-9月份)。采用全血基因组DNA提取试剂盒(离心柱型)提取DNA。4℃过夜使DNA充分溶解,然后储存于-20℃备用。
引物设计及PCR扩增
HO-1基因启动子区5′端poly(GT)n区域扩增：引物设计参照文献(由上海Invitrogen生物工程公司合成)：上游：5'-AGAGCCTGCAGCTTCTCAGA-3';下游：5'-ACAAAGTCTGGCCATAGGAC-3',扩增片段大小为67bp+(GT)n。
PCR反应程序：总量50u1,其中10×bufer 5ul、25 mmol／L MgCl23ul、2.5 mmol／LdNTP 4ul、50umol／L正、反引物各0.25 ul、5U／uL TaqDNA聚合酶0.3ul、基因组DNA 2ul、无菌双蒸水补足50ul。PCR扩增条件：94℃预变性5 min,94℃变性30 s、56℃退火30s、72℃延伸1 min共30个循环,最后72℃延伸5min。
PCR产物用1.5%琼脂糖凝胶电泳鉴定,电泳电压为100 V,时间35min。电泳后,对凝胶扫描拍照。测量已知DNA分子量Marker的迁移率作为自变量(x),其长度(bp)为因变量拟合标准曲线。测量加样孔前沿至DNA条带间的距离,代入标准曲线,求得待测DNA片段长度。根据文献计算(GT)n重复拷贝数n=(扩增的DNA片段长度-67)／2,n值的不同分为两组人群,n≤27为小量重复序列(S等位基因)；>27为大量重复序列(L等位基因)。
所有志愿者均抽取外周静脉血5ml,以3000r／min离心15 min后分离血清,冷冻于-80℃待测。MDA和TAOC均采用分光光度计测定。MDA测定采用硫代巴比妥酸法,TAOC测定,采用Fe3+／Fe2+还原法。
结果：本研究显示,1.A组中血红素加氧酶-1基因启动子L型出现频率较C组高,S型基因出现频率较低(P<0.05)；B组中血红素加氧酶-1基因启动子L型出现频率较D组高,S型基因出现频率较低(P<0.05)；湿热组中HO-1基因启动子的L型基因出现频率较对照组高,S型基因出现频率较低(P<0.01)。2.广东籍志愿者组HO-1基因启动子的L型等位基因频率显著高于非广东籍组(P<0.05)。3.HO-1基因启动子L型基因携带者TAOC较S型基因携带者低、而MDA含量较高(P<0.01)。4.湿热组TAOC较对照组低,而MDA含量较高(P<0.01)。
结论：该研究发现湿热组与对照组,广东籍组与非广东籍组HO-1基因启动子区L型等位基因频率分布有显著差异。提示HO-1基因启动子微卫星多态具有地理差异。HO-1基因启动子L型增加湿热证的易感性,HO-1基因启动子L型基因是湿热体质相关基因、湿热证易感基因本身或其一部分,是广东汉族湿热体质、湿热证易感性的遗传学基础之一。此外,HO-1基因启动子L型基因携带者抗氧化防御能力降低,而抗氧化能力降低是湿热证的病理基础之一,由此推测HO-1基因启动子L型基因可能通过影响机体的抗氧化损伤反应而导致湿热证的易感。
Lingnan belongs to subtropical zone, near the South China Sea, with low-lying land and Nanling Mountains, forming a unique geographical environment. Lingnan region is in low latitude, close to the equatorial zone in China, sunshine and solar radiation is strong. The climate is hot, humid and rainy, the average temperature between 20.4 and 23.1℃, the annual rainfall is from 1500 to 2000 mm, it is a famous rainy region in China. Four Seasons division is not obvious, with long summer and warm winter, and the duration of high temperature in a day is long, the average temperature is high, resulting in heat body constitution of Lingnan people. The annual average relative humidity of Guangzhou and Pearl River Delta zone is 78%, and it can reach 85% between March and August. The hot and humid climate exceeds the regulation limit of the body leads to the formation of damp-heat pathogenic factors easily. Furthermore, people in Guangdong like swimming, bathing, eating fish, shrimp, snail and oyster as well as many other wet feminine goods, with the addition of drinking raw frozen things, affecting the individual digestion and absorption function of spleen and stomach. Wet obstructs spleen and stomach, leading to damp-heat body constitution. The geographical environment, climate factors, eating habits, living custom, body constitution in Lingnan leads to the occurrence of damp-heat syndrome.
Body constitution refers to the relatively stable complex of specific physical quality and psychological quality in aspects of shape, structure, function, metabolism, which formed in the process of growth and development as well as under the effect of heredity and the environmental factors. It is not only affected by genetic factors, but also by acquired environmental factors. From the point of TCM theory, body constitution is important material foundation for the development of syndrome. The particularity of the individual body constitution usually determines the susceptibility to certain kind of pathogenic factors and tendentiousness of lesion type. To a certain extent, body constitution determines the occurrence and development as well as prognosis of the disease, determines the type, conversion, and outcome of the syndrome.
Individual characteristic of body constitution gradually developed based on hereditary factor, under the influence of acquired disposition, through influence and change of nature, society, situation, catering and many other factors. Body constitution difference determined by the genetic background is an important condition for maintaining relative stability of individual body constitution feature.
Human genome sequence variation is one of the basic characteristics of the genome. It is the gene polymorphisms, genomic sequence diversity that constitutes the genetics foundation of susceptibility to diseases, reaction to drug and environmental factors of different individuals and groups. The appearance of gene polymorphisms is the inevitable result of human evolution and adaptation to the environment. Meanwhile, the diversity of it in the population is the internal basis of different susceptibility to diseases for different individual.
The climate of Guangdong region is hot and rainy, thus, forming a high temperature and humidity (damp-heat) climate characteristics. The body in such an environment can occur heat stress response. Heme oxygenase-1 (HO-1) is a highly conserved stress protein during the evolution, play an important role to maintain the stability of the body. Its main function is to improve the cellular tolerance capability to stress factors, so that cells maintain normal physiological function, increase defense and adaptation capability to lethal stimuli. It catalyzes the degradation of heme, a potent oxidant, into biliverdin, carbon monoxide (CO) and free iron. HO-1 is a protective factor which exerts anti-inflammatory, antioxidant, anti-proliferative effect.
(GT)n dinucleotide repeat sequence length polymorphism in the HO-1 gene promoter influences the susceptibility to pulmonary diseases, cardiovascular diseases, cerebrovascular diseases, tumor and many other diseases. After suffering external and internal stimuli as well as injury, different responses occur in carriers with different lengths (GT)n repeats, which affects the individual adaptive capacity, formation of the body constitution, the susceptibility and tolerance to many diseases, influence the reaction to heat stress response, the adaptive capacity to high dampness and high heat as well as the susceptibility to damp-heat syndrome. HO-1 gene promoter microsatellite polymorphism not only reflects the genetic factors, but also is closely related with environmental factors. HO-1 gene may be candidate gene for the research of body constitution, susceptibility to syndrome. Thus, we investigated whether there was any association between heme oxygenase-1 (HO-I) gene promoter microsatellite polymorphism and susceptibility to damp-heat syndrome. Total antioxidant capacity (TAOC) in the serum could reflect the individuals' capacity against oxidant, and malondialdehyde (MDA) could reflect the extent of peroxidation reaction in the body.
Objective:To investigate whether there is any association between heme oxygenase-1 (HO-I) gene promoter microsatellite polymorphism and susceptibility to damp-heat syndrome, geographical environment, oxidative stress; investigate the relationship between damp-heat syndrome and oxidative stress.
Methods:With informed consent signed, refering to the standards of normal body constitution and damp-heat body constitution, we selected unrelated Han Chinese volunteers without positive diseases.
Inclusion criteria:We conducted health survey of family members of Guangdong Han family members that were more than 18 years old (mainly 30-40 years old), who has been living in Guangdong Province, and both parents of the surveyed subjects were Cantonese. Non-Guangdong Han Chinese who have lived in Guangdong province less than five years; both parents of the surveyed subjects were non-Guangdong Chinese. NO positive organic disease was found in the last year. All the volunteers participated in the project voluntarily, and signed the informed consent.
Exclusion criteria:Non-Guangdong Han Chinese who have lived in Guangdong province more than five people; less than 18 years old; other ethnic groups except the Han Chinese; one parents of the volunteer was Guangdong native; volunteer suffered from respiratory, digestive, cardiovascular, urinary, nervous, reproductive system diseases; was in the fever (including the common cold); routine laboratory of heart, liver, lung, kidney, blood lipids, blood sugar, etc was abnormal; pregnant women, lactating women; subjects did not sign informed consent.
The criteria of damp-heat body constitution refers to Classification and Determination of TCM body constitution, Chinese Medicine Clinical Research Drug guiding principle (Provisional Regulations) issued in 2002 and the related criteria draw up by splenogastric research institution of Guangzhou University of Chinese Medicine. Cardinal manifestations:yellow tongue fur, greasy tongue fur, thick and foul fur, slippery and fast pulse. Minor manifestations:dirty and oily complexion, acne prone, bitter and sticky mouth, feeling thirst but do not want to drink, heavy feeling of limbs and trunk, epigastric distension and depression, chest distress, viscid and bad stool, yellow and little urine. Volunteers with one cardinal manifestation and three minor manifestations (or more than that), or with two cardinal manifestations and two minor manifestations (or more than that) belonged to volunteers with damp-heat body constitution.
Selection criteria of control group:with moist and lustrous complexion and skin, dense, dense and shiny hair, bright eyed, energetic, good appetite, sleep well, normal urine and stool, medium body, usually less illness, light red tongue, thin white fur, mild and strong pulse.
There were twenty Cantonese volunteers with damp-heat body constitution in group A, twenty volunteers with damp-heat body constitution who came from other provinces in group B, fifteen healthy control volunteers came from Guangdong province in group C, fifteen healthy control volunteers came from other provinces in group D. Group A and group B belonged to damp-heat group, 40 people in total; group C and group D belonged to control group,30 people in total. People in group A and group C were Cantonese,35 people in total; people in group B and group D were from other province,35 people in total. All the volunteers signed the informed consent for the present study. The study was approved by the Guangzhou University of Chinese Medicine Ethics Committee. There is no difference in gender and age between the two groups.
The survey site was Guangzhou city; the time of the investigation was from spring equinox to the autumnal equinox (3-9 months).
Fasting venous blood sample was extracted from volunteers met the inclusion criteria in each group, blood extracting time was from spring equinox to the autumnal equinox (3-9 months). Genomic DNA was extracted by using whole blood genomic DNA extraction kit (centrifugal column), dissolved DNA fully at 4℃overnight, stored at -20℃for use.
The 5'-flanking region containing (GT)nrepeats of the HO-1 gene was amplified by PCR according to the published procedure (The primer was synthesized by Shanghai Invitrogen Biological Engineering Company.),
sense primer,5'-AGAGCCTGCAGCTTCTCAGA-3',
antisense primer,5'-ACAAAGTCTGGCCATAGGAC-3',
PCR reaction program:total 50ul, 10×bufer 5ul,25 mmol/L MgCl23ul,2.5 mmol/L dNTP 4ul,50umol/L sense primer and anti-sense primer 0.25ul respectively,5U/uL TaqDNA polymerase 0.3ul, genomic DNA 2ul, using sterile distilled water to make up to 50ul.
Reaction conditions:denaturation at 94℃in advance for 3 minutes, then started the cycle, denaturation at 94℃for 30 seconds, annealing at 58℃for 30 seconds, and elongation at 72℃for 1 minute. Altogether 35 cycles were performed, elongation at 72℃for 5 minutes at last. The PCR amplification product was analyzed by using agarose gel electrophoresis (100 V,35 minutes) together with DNA ladder (size range 100-600bp). The PCR products was analyzed with Automatic Gel Imaging System (G:BOX). The allele frequency of (GT)n repeats in HO-1 gene promotor was analyzed by the GeneTool Analysis software (PE Applied Biosystems). The allelic repeats were divided into subclasses: short repeats (S) (27 repeats), L-allele.
5ml peripheral venous blood was extracted from each volunteers, serum was separated after centrifugation 3 OOOr/min,15 min, frozen at-80℃, preparing to be tested. Malondialdehyde (MDA) and total antioxidant capacity (TAOC) were measured by spectrophotometer. MDA was measured through thiobarbituric acid method, TAOC was measured by using Fe3+/Fe2+reduction method.
Results
1. The frequency of L allele of HO-1 was higher in group A than that in group C, while the frequency of S allele was lower (P<0.05). The frequency of L allele of HO-1 was higher in group B than that in group D, while the frequency of S allele was lower (P<0.05). The frequency of L allele of HO-1 was higher in the damp-heat syndrome group than that in healthy control group, while the frequency of S allele was lower (P<0.01).
2. The frequency of L allele of HO-1 was higher in Guangdong Han Chinese than that in non-Guangdong Han Chinese, while the frequency of S allele was lower (P<0.05).
3. TAOC of the L allele carriers was lower compared with that of S allele carriers (15.97±0.89 vs 18.75±1.34, P<0.01). While the MDA content of the L allele carriers was higher compared with that of S allele carriers (6.49±0.59 vs 5.13±0.47, P<0.01)
4. Total antioxidant capacity (TAOC) was lower in the damp-heat syndrome group compared with that in non-damp-heat syndrome group (16.80±1.41 vs 18.01±2.04, P<0.01). Meanwhile, the MDA content was higher in the damp-heat syndrome group compared with that in non-damp-heat syndrome group (6.09±0.95 vs 5.48±0.60, P<0.01).
Conclusion:The distribution of L allele between damp-heat syndrome group and non-damp-heat syndrome group, between Guangdong Chinese and non-Guangdong Chinese, was statistically different. This indicated that microsatellite polymorphism in the HO-1 gene promoter was geography different. L allele in the HO-1 gene promoter increased the susceptibility to damp-heat syndrome. L allele in the HO-1 gene promoter was damp-heat body constitution related gene and predisposing gene of damp-heat syndrome, or part of the predisposing gene. It was one of the genetic basis of damp-heat body constitution and susceptibility to damp-heat syndrome of Guangdong Han Chinese. In addition, the total antioxidant capacity of L allele carriers in the HO-1 gene promoter reduced, meanwhile, the reduction of antioxidant capacity was one of the pathological basis of damp-heat syndrome, which indicated that L-allele in HO-1 gene promoter might increase the susceptibility to damp-heat syndrome by affecting individual antioxidant stress injury response.
体质是人群中的个体在遗传基础上和缓慢的环境因素作用下,在其生长发育过程中所形成的形态、结构、功能、代谢等方面相对稳定的特定躯体素质与心理素质的综合体。它既受先天遗传因素的影响,又受后天环境因素的影响。中医理论认为,体质是证候产生的重要基础,个体体质的特殊性,往往决定着他对某种致病因子的易感性及其所产生病变类型的倾向性。在某种程度上,体质因素决定着疾病的发生、发展和预后,决定证候的类型、转化和转归。每一个人体质的个体特点,都是以遗传因素为基础,在后天生长条件的影响下,经过自然、社会、境遇、饮食等诸多因素的影响和变迁,逐渐发展起来的。由遗传背景所决定的体质差异是维持个体体质特征相对稳定的重要条件。人类基因组序列中的变异是基因组的基本特征之一,而正是这种基因的多态性,即基因组序列的差异构成了不同个体与群体对疾病的易感性、对药物与环境因子不同反应的遗传学基础。它的出现是人类进化和适应环境的必然结果。同时它在人群中的多样性成为不同个体对疾病易感性不同的内因基础。
广东地区气候炎热、高温多雨,因而形成了高温高湿(湿热)的气候特征,机体在这种高温高湿的环境下可发生热应激反应(heat stress response)。血红素加氧酶-1(heme oxygenase-1, HO-1)是一种在进化过程中高度保守的应激蛋白,对维持机体的自身稳定性起重要作用。其主要功能是提高细胞对应激因素的耐受,使细胞维持正常的生理功能,增加细胞对致死性刺激的防御和适应能力。HO-1催化氧化剂血红素的降解,生成胆绿素、一氧化碳、和游离铁。HO-1是一个保护因子,具有抗炎、抗氧化、抗增殖效应。
人HO-1基因启动子区GT双核苷酸重复序列长度多态性影响个体对肺部疾病、心脑血管疾病、肿瘤等多种疾病的易感性。不同长度(GT)n重复序列携带者在机体受到内外界刺激、损伤后发生的反应不同,从而影响机体的适应能力、体质的形成以及对诸多疾病的易感性、耐受性,影响机体对热应激的反应,对高温高湿的适应能力和对湿热证的易感性。血红素加氧酶-1(HO-1)基因启动子微卫星多态性既反映了遗传因素,同时与环境因素密切相关。因此,我们研究了血红素加氧酶-1基因启动子微卫星多态性与广东汉族人湿热证易感性的关系。血清总抗氧化能力(TAOC)测定能显示机体抗氧化防御能力,丙二醛(MDA)可以反映过氧化反应进行的程度。
目的：HO-1基因启动子微卫星多态性与广东汉族人湿热证易感性、地理环境、氧化应激的关系；研究湿热证与氧化应激反应的关系。
方法：参考平和体质、湿热体质判别标准,在志愿者知情同意的情况下收集无阳性病变,无血缘关系的汉族志愿者。
纳入标准：对年龄在18周岁以上(以30-40岁为主),在广东省生活的广东籍汉族家庭成员进行健康调查,受试者的父母籍贯均为广东籍；在广东省居住小于五年的中国非广东籍(主要为北方各省份)汉族人群；受试者的父母均为非广东籍：近一年体检无阳性器质性病变；自愿且能够参加该项目,所有志愿者均需签订知情同意书。
排除标准：非广东籍(主要为北方各省份)汉族人在广东省居住长于五年的人群；年龄18周岁以下；除中国汉族以外的其他民族；志愿者的父母籍贯一方为广东籍；患有呼吸、消化、心脑血管、泌尿、神经、生殖等系统疾病；处于发热期(包括感冒)；心、肝、肺、肾、血脂、血糖等常规实验室检查异常；孕妇、哺乳期妇女；未获得知情同意者。
湿热体质的判定标准参照《中医体质分类与判定》标准,2002年《中药新药临床研究指导原则(试行)》及广州中医药大学脾胃研究所相关标准,制定如下：
主要表现：苔黄、苔腻或厚浊,脉滑数。次要表现：面垢油光,易生痤疮,口苦而粘；渴而少饮：肢体困重；脘闷腹胀；胸闷；大便粘滞不爽；小便黄短。
具备1个主要表现+3个(或以上)次要表现；2个主要表现+2个(或以上)次要表现,即可判定为湿热体质。
对照组选择标准参照《中医体质分类与判定》平和质判别标准：面色、肤色润泽,头发稠密有光泽,目光有神、精力充沛、胃纳佳、睡眠安、二便调、体态适中、平素少病、舌色淡红,苔薄白,脉和缓有力。
分为A、B、C、D组,A组为广东籍湿热体质组,20例；B组为非广东籍湿热体质组,20例；C组为广东籍平和体质组,15例；D组为非广东籍平和体质组15例。A组、B组为湿热体质组,共40例,C组、D组为对照组(平和体质组),共30例；A组、C组为广东籍组,共35人,B组、D组为非广东籍组,共35人。各组性别、年龄无差异,具有可比性。
调查地点选择广东省广州市；调查时间选择在的春分至秋分期间(5-9月份)。
符合纳入标准的各组志愿者空腹静脉采血,采血时间在春分至秋分期间(5-9月份)。采用全血基因组DNA提取试剂盒(离心柱型)提取DNA。4℃过夜使DNA充分溶解,然后储存于-20℃备用。
引物设计及PCR扩增
HO-1基因启动子区5′端poly(GT)n区域扩增：引物设计参照文献(由上海Invitrogen生物工程公司合成)：上游：5'-AGAGCCTGCAGCTTCTCAGA-3';下游：5'-ACAAAGTCTGGCCATAGGAC-3',扩增片段大小为67bp+(GT)n。
PCR反应程序：总量50u1,其中10×bufer 5ul、25 mmol／L MgCl23ul、2.5 mmol／LdNTP 4ul、50umol／L正、反引物各0.25 ul、5U／uL TaqDNA聚合酶0.3ul、基因组DNA 2ul、无菌双蒸水补足50ul。PCR扩增条件：94℃预变性5 min,94℃变性30 s、56℃退火30s、72℃延伸1 min共30个循环,最后72℃延伸5min。
PCR产物用1.5%琼脂糖凝胶电泳鉴定,电泳电压为100 V,时间35min。电泳后,对凝胶扫描拍照。测量已知DNA分子量Marker的迁移率作为自变量(x),其长度(bp)为因变量拟合标准曲线。测量加样孔前沿至DNA条带间的距离,代入标准曲线,求得待测DNA片段长度。根据文献计算(GT)n重复拷贝数n=(扩增的DNA片段长度-67)／2,n值的不同分为两组人群,n≤27为小量重复序列(S等位基因)；>27为大量重复序列(L等位基因)。
所有志愿者均抽取外周静脉血5ml,以3000r／min离心15 min后分离血清,冷冻于-80℃待测。MDA和TAOC均采用分光光度计测定。MDA测定采用硫代巴比妥酸法,TAOC测定,采用Fe3+／Fe2+还原法。
结果：本研究显示,1.A组中血红素加氧酶-1基因启动子L型出现频率较C组高,S型基因出现频率较低(P<0.05)；B组中血红素加氧酶-1基因启动子L型出现频率较D组高,S型基因出现频率较低(P<0.05)；湿热组中HO-1基因启动子的L型基因出现频率较对照组高,S型基因出现频率较低(P<0.01)。2.广东籍志愿者组HO-1基因启动子的L型等位基因频率显著高于非广东籍组(P<0.05)。3.HO-1基因启动子L型基因携带者TAOC较S型基因携带者低、而MDA含量较高(P<0.01)。4.湿热组TAOC较对照组低,而MDA含量较高(P<0.01)。
结论：该研究发现湿热组与对照组,广东籍组与非广东籍组HO-1基因启动子区L型等位基因频率分布有显著差异。提示HO-1基因启动子微卫星多态具有地理差异。HO-1基因启动子L型增加湿热证的易感性,HO-1基因启动子L型基因是湿热体质相关基因、湿热证易感基因本身或其一部分,是广东汉族湿热体质、湿热证易感性的遗传学基础之一。此外,HO-1基因启动子L型基因携带者抗氧化防御能力降低,而抗氧化能力降低是湿热证的病理基础之一,由此推测HO-1基因启动子L型基因可能通过影响机体的抗氧化损伤反应而导致湿热证的易感。
Lingnan belongs to subtropical zone, near the South China Sea, with low-lying land and Nanling Mountains, forming a unique geographical environment. Lingnan region is in low latitude, close to the equatorial zone in China, sunshine and solar radiation is strong. The climate is hot, humid and rainy, the average temperature between 20.4 and 23.1℃, the annual rainfall is from 1500 to 2000 mm, it is a famous rainy region in China. Four Seasons division is not obvious, with long summer and warm winter, and the duration of high temperature in a day is long, the average temperature is high, resulting in heat body constitution of Lingnan people. The annual average relative humidity of Guangzhou and Pearl River Delta zone is 78%, and it can reach 85% between March and August. The hot and humid climate exceeds the regulation limit of the body leads to the formation of damp-heat pathogenic factors easily. Furthermore, people in Guangdong like swimming, bathing, eating fish, shrimp, snail and oyster as well as many other wet feminine goods, with the addition of drinking raw frozen things, affecting the individual digestion and absorption function of spleen and stomach. Wet obstructs spleen and stomach, leading to damp-heat body constitution. The geographical environment, climate factors, eating habits, living custom, body constitution in Lingnan leads to the occurrence of damp-heat syndrome.
Body constitution refers to the relatively stable complex of specific physical quality and psychological quality in aspects of shape, structure, function, metabolism, which formed in the process of growth and development as well as under the effect of heredity and the environmental factors. It is not only affected by genetic factors, but also by acquired environmental factors. From the point of TCM theory, body constitution is important material foundation for the development of syndrome. The particularity of the individual body constitution usually determines the susceptibility to certain kind of pathogenic factors and tendentiousness of lesion type. To a certain extent, body constitution determines the occurrence and development as well as prognosis of the disease, determines the type, conversion, and outcome of the syndrome.
Individual characteristic of body constitution gradually developed based on hereditary factor, under the influence of acquired disposition, through influence and change of nature, society, situation, catering and many other factors. Body constitution difference determined by the genetic background is an important condition for maintaining relative stability of individual body constitution feature.
Human genome sequence variation is one of the basic characteristics of the genome. It is the gene polymorphisms, genomic sequence diversity that constitutes the genetics foundation of susceptibility to diseases, reaction to drug and environmental factors of different individuals and groups. The appearance of gene polymorphisms is the inevitable result of human evolution and adaptation to the environment. Meanwhile, the diversity of it in the population is the internal basis of different susceptibility to diseases for different individual.
The climate of Guangdong region is hot and rainy, thus, forming a high temperature and humidity (damp-heat) climate characteristics. The body in such an environment can occur heat stress response. Heme oxygenase-1 (HO-1) is a highly conserved stress protein during the evolution, play an important role to maintain the stability of the body. Its main function is to improve the cellular tolerance capability to stress factors, so that cells maintain normal physiological function, increase defense and adaptation capability to lethal stimuli. It catalyzes the degradation of heme, a potent oxidant, into biliverdin, carbon monoxide (CO) and free iron. HO-1 is a protective factor which exerts anti-inflammatory, antioxidant, anti-proliferative effect.
(GT)n dinucleotide repeat sequence length polymorphism in the HO-1 gene promoter influences the susceptibility to pulmonary diseases, cardiovascular diseases, cerebrovascular diseases, tumor and many other diseases. After suffering external and internal stimuli as well as injury, different responses occur in carriers with different lengths (GT)n repeats, which affects the individual adaptive capacity, formation of the body constitution, the susceptibility and tolerance to many diseases, influence the reaction to heat stress response, the adaptive capacity to high dampness and high heat as well as the susceptibility to damp-heat syndrome. HO-1 gene promoter microsatellite polymorphism not only reflects the genetic factors, but also is closely related with environmental factors. HO-1 gene may be candidate gene for the research of body constitution, susceptibility to syndrome. Thus, we investigated whether there was any association between heme oxygenase-1 (HO-I) gene promoter microsatellite polymorphism and susceptibility to damp-heat syndrome. Total antioxidant capacity (TAOC) in the serum could reflect the individuals' capacity against oxidant, and malondialdehyde (MDA) could reflect the extent of peroxidation reaction in the body.
Objective:To investigate whether there is any association between heme oxygenase-1 (HO-I) gene promoter microsatellite polymorphism and susceptibility to damp-heat syndrome, geographical environment, oxidative stress; investigate the relationship between damp-heat syndrome and oxidative stress.
Methods:With informed consent signed, refering to the standards of normal body constitution and damp-heat body constitution, we selected unrelated Han Chinese volunteers without positive diseases.
Inclusion criteria:We conducted health survey of family members of Guangdong Han family members that were more than 18 years old (mainly 30-40 years old), who has been living in Guangdong Province, and both parents of the surveyed subjects were Cantonese. Non-Guangdong Han Chinese who have lived in Guangdong province less than five years; both parents of the surveyed subjects were non-Guangdong Chinese. NO positive organic disease was found in the last year. All the volunteers participated in the project voluntarily, and signed the informed consent.
Exclusion criteria:Non-Guangdong Han Chinese who have lived in Guangdong province more than five people; less than 18 years old; other ethnic groups except the Han Chinese; one parents of the volunteer was Guangdong native; volunteer suffered from respiratory, digestive, cardiovascular, urinary, nervous, reproductive system diseases; was in the fever (including the common cold); routine laboratory of heart, liver, lung, kidney, blood lipids, blood sugar, etc was abnormal; pregnant women, lactating women; subjects did not sign informed consent.
The criteria of damp-heat body constitution refers to Classification and Determination of TCM body constitution, Chinese Medicine Clinical Research Drug guiding principle (Provisional Regulations) issued in 2002 and the related criteria draw up by splenogastric research institution of Guangzhou University of Chinese Medicine. Cardinal manifestations:yellow tongue fur, greasy tongue fur, thick and foul fur, slippery and fast pulse. Minor manifestations:dirty and oily complexion, acne prone, bitter and sticky mouth, feeling thirst but do not want to drink, heavy feeling of limbs and trunk, epigastric distension and depression, chest distress, viscid and bad stool, yellow and little urine. Volunteers with one cardinal manifestation and three minor manifestations (or more than that), or with two cardinal manifestations and two minor manifestations (or more than that) belonged to volunteers with damp-heat body constitution.
Selection criteria of control group:with moist and lustrous complexion and skin, dense, dense and shiny hair, bright eyed, energetic, good appetite, sleep well, normal urine and stool, medium body, usually less illness, light red tongue, thin white fur, mild and strong pulse.
There were twenty Cantonese volunteers with damp-heat body constitution in group A, twenty volunteers with damp-heat body constitution who came from other provinces in group B, fifteen healthy control volunteers came from Guangdong province in group C, fifteen healthy control volunteers came from other provinces in group D. Group A and group B belonged to damp-heat group, 40 people in total; group C and group D belonged to control group,30 people in total. People in group A and group C were Cantonese,35 people in total; people in group B and group D were from other province,35 people in total. All the volunteers signed the informed consent for the present study. The study was approved by the Guangzhou University of Chinese Medicine Ethics Committee. There is no difference in gender and age between the two groups.
The survey site was Guangzhou city; the time of the investigation was from spring equinox to the autumnal equinox (3-9 months).
Fasting venous blood sample was extracted from volunteers met the inclusion criteria in each group, blood extracting time was from spring equinox to the autumnal equinox (3-9 months). Genomic DNA was extracted by using whole blood genomic DNA extraction kit (centrifugal column), dissolved DNA fully at 4℃overnight, stored at -20℃for use.
The 5'-flanking region containing (GT)nrepeats of the HO-1 gene was amplified by PCR according to the published procedure (The primer was synthesized by Shanghai Invitrogen Biological Engineering Company.),
sense primer,5'-AGAGCCTGCAGCTTCTCAGA-3',
antisense primer,5'-ACAAAGTCTGGCCATAGGAC-3',
PCR reaction program:total 50ul, 10×bufer 5ul,25 mmol/L MgCl23ul,2.5 mmol/L dNTP 4ul,50umol/L sense primer and anti-sense primer 0.25ul respectively,5U/uL TaqDNA polymerase 0.3ul, genomic DNA 2ul, using sterile distilled water to make up to 50ul.
Reaction conditions:denaturation at 94℃in advance for 3 minutes, then started the cycle, denaturation at 94℃for 30 seconds, annealing at 58℃for 30 seconds, and elongation at 72℃for 1 minute. Altogether 35 cycles were performed, elongation at 72℃for 5 minutes at last. The PCR amplification product was analyzed by using agarose gel electrophoresis (100 V,35 minutes) together with DNA ladder (size range 100-600bp). The PCR products was analyzed with Automatic Gel Imaging System (G:BOX). The allele frequency of (GT)n repeats in HO-1 gene promotor was analyzed by the GeneTool Analysis software (PE Applied Biosystems). The allelic repeats were divided into subclasses: short repeats (S) (27 repeats), L-allele.
5ml peripheral venous blood was extracted from each volunteers, serum was separated after centrifugation 3 OOOr/min,15 min, frozen at-80℃, preparing to be tested. Malondialdehyde (MDA) and total antioxidant capacity (TAOC) were measured by spectrophotometer. MDA was measured through thiobarbituric acid method, TAOC was measured by using Fe3+/Fe2+reduction method.
Results
1. The frequency of L allele of HO-1 was higher in group A than that in group C, while the frequency of S allele was lower (P<0.05). The frequency of L allele of HO-1 was higher in group B than that in group D, while the frequency of S allele was lower (P<0.05). The frequency of L allele of HO-1 was higher in the damp-heat syndrome group than that in healthy control group, while the frequency of S allele was lower (P<0.01).
2. The frequency of L allele of HO-1 was higher in Guangdong Han Chinese than that in non-Guangdong Han Chinese, while the frequency of S allele was lower (P<0.05).
3. TAOC of the L allele carriers was lower compared with that of S allele carriers (15.97±0.89 vs 18.75±1.34, P<0.01). While the MDA content of the L allele carriers was higher compared with that of S allele carriers (6.49±0.59 vs 5.13±0.47, P<0.01)
4. Total antioxidant capacity (TAOC) was lower in the damp-heat syndrome group compared with that in non-damp-heat syndrome group (16.80±1.41 vs 18.01±2.04, P<0.01). Meanwhile, the MDA content was higher in the damp-heat syndrome group compared with that in non-damp-heat syndrome group (6.09±0.95 vs 5.48±0.60, P<0.01).
Conclusion:The distribution of L allele between damp-heat syndrome group and non-damp-heat syndrome group, between Guangdong Chinese and non-Guangdong Chinese, was statistically different. This indicated that microsatellite polymorphism in the HO-1 gene promoter was geography different. L allele in the HO-1 gene promoter increased the susceptibility to damp-heat syndrome. L allele in the HO-1 gene promoter was damp-heat body constitution related gene and predisposing gene of damp-heat syndrome, or part of the predisposing gene. It was one of the genetic basis of damp-heat body constitution and susceptibility to damp-heat syndrome of Guangdong Han Chinese. In addition, the total antioxidant capacity of L allele carriers in the HO-1 gene promoter reduced, meanwhile, the reduction of antioxidant capacity was one of the pathological basis of damp-heat syndrome, which indicated that L-allele in HO-1 gene promoter might increase the susceptibility to damp-heat syndrome by affecting individual antioxidant stress injury response.
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