【作者】 戴江红；

【导师】 姚华； 严卫丽；

【作者基本信息】 新疆医科大学 ， 劳动卫生与环境卫生学， 2009， 博士

【摘要】 目的：世界范围儿童肥胖的流行给公共卫生带来了新的挑战,肥胖不仅属于一种疾病,还是引起2型糖尿病、心脏病、代谢综合征、高血压、脑卒中和一些癌症发病和死亡危险增加的一个重要原因。体重指数(Body mass index, BMI, kg/m2)是目前国际上筛查超重和肥胖的常用指标,它与机体脂肪含量、远期健康效应和疾病危险度密切相关,具有计算简便、测量容易、成本低廉、重现性好等显著优点,在群体筛查和大规模流行病学调查评价肥胖时被广为采纳和应用。儿童青少年处于生长发育的快速增长期,不同年龄和性别需要不同的BMI标准。由于不同种族或民族人群在同一BMI水平时肥胖相关疾病发生危险和死亡危险不同,BMI分类标准也因而存在人群特异性。维吾尔族(维族)是新疆的主要少数民族,与汉族有着不同的遗传背景、生活习惯和饮食方式,这些都有肥胖的发生密切相关,是否需要建立同一地区不同民族儿童青少年的BMI分类标准值得深入研究。肥胖病因复杂,其发生机理的研究已经深入到基因调控水平,Perilipin是脂肪代谢调节通路中一种重要的调控蛋白,由PLIN基因编码,已有多项研究结果表明PLIN基因与肥胖发生密切相关,但维族人群PLIN基因与肥胖关系尚未见报道。本研究从基因多态性的角度分析维、汉儿童青少年肥胖与PLIN基因的关联,并进一步探讨非干预和干预条件下,PLIN基因多态性与肥胖状态改变的相关关系；基因对干预效果影响的研究,可以为制定肥胖干预的个体化方案提供理论依据。方法：1)用分层整群抽样方法调查乌鲁木齐市7-18岁维、汉中小学生9146人,利用国际通用的国际肥胖工作组(International Obesity Task Force, IOTF)在制定儿童超重肥胖参考标准采用的偏度-中位数-变异系数法(λmedian coefficient of variation method, LMS法),绘制维、汉民族7-18岁人群性别、年龄别BMI百分位曲线,确定18岁时分别通过国际肥胖工作组(IOTF)和中国肥胖问题工作组(Work Group on Obesity in China, WGOC)成年人超重、肥胖标准的特殊百分位数曲线,由此获得两民族7-18岁人群超重和肥胖的界值标准；2)以现况调查筛检出的肥胖人群为基础,进行成组设计的病例对照研究,检测616例维、汉儿童青少年PLIN基因四种标签SNPs:rs1052700A/T (SNP1)、rs8179043A/G (SNP2)、rs6496589C/G (SNP3)和rs4578621C/G (SNP4)的基因分型及频率,并对维、汉研究对象随访一年,观察在自然生长条件下人群肥胖状态的改变,分析PLIN基因四种标签SNP与肥胖、肥胖相关表型及肥胖状态变化的关联；3)以同伴教育为主的健康教育和增加50分钟规范体育锻炼活动作为两种主要干预手段,将364名7-11岁维、汉族学生分为对照组、干预组1(单纯教育组)和干预组2(教育+锻炼组),实施以学校为场所的干预试验,并对为期7个月的干预效果进行评价,分析PLIN基因多态性对干预效果的影响。结果：1)18岁时通过25及30kg/m2的百分位曲线：维族男生为P94.46和P99.58,维族女生为P92.44和P99.64,汉族男生为P85.05和P97.26,汉族女生为P90.92和P99.03；通过24及28kg/m2的百分位曲线维族男生为P90.54和P98.86,维族女生为P86.96和P98.77,汉族男生为P78.98和P94.72,汉族女生为P86.15和P97.56；2)对乌鲁木齐市中小学生而言,汉族学生使用WGOC标准能及时发现BMI超标人群,而维族学生无论使用WGOC或IOTF标准,它们的界值标准均偏高,灵敏度相对偏低,其筛查结果可能会遗漏一部分高危人群,低估人群的超重率和肥胖率,削弱对该群体预防肥胖的警惕性,从而影响筛检效应；3)维族人群PLIN基因SNP1与肥胖以及腹型肥胖的发生相关,在控制性别、年龄、甘油三酯和胰岛素等因素后,这种关联性依然存在,以AA作为对照,基因型AT和TT者发生肥胖的风险分别为4.485(1.670,12.045)和3.096(1.161,8.252),发生腹型肥胖(以腰围划分)的风险分别为3.709(1.377,9.989)和3.282(1.226,8.784)；SNP1的AT基因型者、携带SNP3的G等位基因者舒张压水平较高。但是汉族人群并未发现上述关联性的存在；4)随访一年,观察自然生长条件下人群肥胖状态的改变,发现与SNP1的AA基因型相比,AT基因型者由肥胖转为正常发生的可能性是体重保持正常可能性的3.987倍,SNP3的CC基因型与CG+GG型相比,保持体重正常是保持肥胖状态发生可能性的3.03倍。PLIN基因与自然生长条件下肥胖相关测量的变化量有关联,主要表现在SNP3对BMI的绝对增长量和增长速度有影响,CC基因型者BMI增加量和增加速度低于CG+GG基因型者,即携带SNP3等位基因G者BMI的增长幅度大、速度快,在扣除了民族、年龄、肥胖状态等因素的作用,SNP3基因型对BMI的变化量仍然有影响；5)为期7个月的干预试验发现单纯教育组和对照组各指标变化无明显不同,而健康教育和体育锻炼结合的干预组与单纯教育组及对照组相比,其BMI增长量和增长速度明显下降,BMI-Z分值增长量也明显降低,并且体育锻炼主要降低肥胖者血压和胆固醇水平,而对正常体重者无影响；6)PLIN基因型不同,儿童干预应答效应不同,参加体育锻炼者中,SNP3的CC基因型与CG及GG基因型者相比,腰围和腰高比的增长量和增长速度较低,而SNP4的CC基因型者BMI、腰围和腰高比的增长量和增长速度比CG及GG基因型者快,调整民族、性别和年龄等因素,这种关联性依然存在；提示SNP3的CC基因型者和携带SNP4的G等位基因者,对体育锻炼在腰围和腰高比降低的应答反应更为敏感。结论：1)BMI分布具有民族特异性,对乌鲁木齐市维族学生超重、肥胖筛查时建议参考使用本研究标准；2)PLIN基因与维族人群肥胖和腹型肥胖密切相关；rs6496589和rs4578621与儿童青少年生长发育过程中肥胖状态的改变有关联；3)单纯依靠健康教育的干预效果不明显,而健康教育和体育锻炼相结合的干预措施可以有效抑制BMI过快增长、减缓肥胖者肥胖程度的加剧,短期即可取得显著效果；4)PLIN基因多态性与干预效果有一定关联,因此,为了达到有效控制肥胖的目的,可以针对具有不同遗传特征的人进行个体化干预。更多还原

【Abstract】 Objective:The worldwide epidemic of childhood obesity is an emerging global public health challenge. Obesity is not only an unhealthy state, but also associated with an increased risk of type 2 diabetes mellitus, heart disease, metabolic syndrome, hypertension, stroke, and certain forms of cancer. Body mass index (BMI; in kg/m2) has achieved international acceptance as a standard for the screening of overweight and obesity. It is closely related to body fat content, long-term health effects and the risk of disease. It has the advantages of simply calculated, easily measured, low-cost and reproducibility. It is widely adopted and applied in the population screening, large-scale epidemiological investigation and assessment of obesity. Children and adolescents are in a period of rapid growth and development, so it is needed to be used the BMI reference norm for defining overweight and obesity according to different ages and genders. Due to different races or ethnic groups, obesity-related diseases have difference between the risk of occurrence and death on the same BMI level, the BMI reference norm is ethnically different. Uygur, the main ethnicity in Xinjiang, has different genetic background, living habits and dietary pattern with Han ethnicity, which are closely related to the occurrence of obesity. It is necessary to establish the BMI reference norm for defining overweight and obesity in different ethnic children and adolescents in the same area. The causes of obesity are complex. The study of mechanism of obesity has reached the level of gene regulation. Perilipin, encoded by the gene PLIN, is an important protein in the regulation of fat metabolism pathway. A number of studies showed that PLIN gene closely related to the occurrence of obesity, and has population specificity. However, it has not previously been reported that PLIN gene is associated with the obesity in Uygur people. The purpose of this study is to investigate whether PLIN gene polymorphisms were associated with obesity and obesity-related changes with and without intervention in school-age children and adolescents with Uygur and Han ethnic backgrounds in Urumqi. The association study of the gene and the effect of intervention, provide a theoretical evidence for drawing up individualized programs of obesity intervention. Methods:1)A total number of 9146 boys and girls in Urumqi, Xinjiang, aged 7～18 years, were recruited by stratifying and clustering sampling from April to June 2004. Using the internationalλmedian coefficient of variation method in the development of overweight children obese reference by the International Obesity Working Group (International Obesity Task Force, IOTF), BMI centile curves with 7～18 age were drawn according to gender and ethnicity. Using LMS software (Tim cole and Huiqi Pan) which were making the centile curves passing through 25kg/m2 and 30kg/m2 (International Obesity Task Force, IOTF), and 24kg/m2 and 28kg/m2 (Work Group on Obesity in China, WGOC) at age of 18 for overweight and obesity respectively, the age and sex specific BMI cutoff points for children with Uygur and Han ethnicities were constructed.2) Based on the obese group screened by the cross-sectional investigation, a group-matched case-control study was carried out. We examined four types of tag single nucleotide polymorphisms (SNPs) at the perilipin (PLIN) locus (rs1052700A/T (SNP1), rs8179043A/G (SNP2), rs6496589C/G (SNP3) and rs4578621C/G (SNP4)) to investigate their association with obesity risk. The study population included 616 subjects of Uygur and Han ethnic children and adolescents in Urumqi. Moreover, by following-up the study subjects for a year, we observed the change of obesity state of subjects under the natural growth and development conditions and tried to analyze the association between PLIN gene polymorphisms and obesity, obesity-related phenotypes and the change of obesity state.3) Adopted two major measures of peer education-based health education and 50 minutes physical activity 3 times a week,364 Uygur and Han ethnic school-aged children aged 7-11 years were divided into three groups, namely control group, the first intervention group (simple health education group) and the second intervention group (health education plus physical activity). In three primary schools, a 7 month-period obesity intervention trial was conducted and the effects of obesity intervention were evaluated. At the same time, the association between PLIN gene polymorphisms and intervention effect was studied. Results:1) The age and sex specific BMI centile curves were drawn for children with Uygur and Han ethnicities. Data showed that BMI increased with age. The centile of BMI curves, P94.46 and P99.58 for Uygur boys, P92.44 and P99.64 for Uygur girls, P85.05 and P97.26 for Han boys, P90.92 and P99.03 for Han girls, which passing through 25kg/m2 and 30kg/m2 by IOTF recommendation at age 18, were constructed. Under the basis of WGOC recommendation, the points that passing through 24kg/m2 and 28kg/m2 at age 18 was P90.54 and P98.86 for Uygur boys, P86.96 and P98.77 for Uygur girls, P78.98 and P94.72 for Han boys, Pg6.i5 and P97.56 for Han girls. The BMI cutoff points for defining overweight and obesity were suggested.2) The WGOC standard is appropriate to identifying overweight and obesity in Han ethnic children and youths in Urumqi. Regardless of the WGOC or IOTF standards, the BMI cutoff points for defining overweight and obesity in Uygur children and youths are not appropriate. The screening trial has relatively low sensitivity and may be missing part of high-risk groups. The prevalence of overweight and obesity may be underestimated. The risk of obesity is not in timely recognized. Thereby the screening effect will be weaken.3) In Uygur people, rs1052700A/T polymorphism was significantly associated with the occurrence of obesity and abdominal obesity after adjusting for covariates including age, sex, insulin, triglyceride and other factors. As compared with genotype AA, the risk with AT and TT genotypes of the occurrence of obesity were 4.485 (1.670,12.045) and 3.096 (1.161, 8.252), the risk of the occurrence of abdominal obesity (divided by waistline) were 3.709 (1.377,9.989) and 3.282 (1.226,8.784). People with AT genotypes of rs1052700 or carrying the G allele of rs6496589 have higher levels of diastolic blood pressure. No significant associations could be found between any of these polymorphisms and the studied phenotypes in Han population.4) By following-up the study subjects for a year, we observed the change of obesity state of subjects under the natural growth and development conditions. We found that the possibility of AT genotype from obesity turning to the normal body weight is 3.987 times to the possibility to maintain normal body weight compared with the AA genotype of rs1052700. Comparing the CC genotype of SNP3 with the CG+GG genotype, the possibility maintaining body weight normally is 3.03 times than the obese state of the possibility of occurrence. Under the natural self-growth condition, PLIN gene has relation to the Obesity-related measurements variable quantities, it mainly manifests that the rs6496589 impacts the absolute amount of growth and the growth rate of the body mass index, the body of CC genotype increment and velocity of increase less than CG+GG Genotype, it also shows the body mass index of the body with allele G the growth rate of large and fast, after adjusting the ethnics, ages, obesity, and other factors, rs6496589 genotype still have an impact on the body mass index of variable quantities.5) In a 7 month-period obesity intervention study, we found that simple health education group and the control group had no significant changes in various indicators. The intervention group combined with health education and physical activity, compared with simple education group and control group, the growth amount and rate of BMI decreased, the BMI-Z score which reflected growth degree of obesity in children and adolescents changes also decreased significantly, it manifested that combination of the health education and physical activity are effective in a short-term. And physical exercise can significantly reduce blood pressure and cholesterol levels among obese group but had no effect on normal weight.6) With the difference of genotypes PLIN, the different response effect of intervention of children had been observed. Among those taking part in physical exercise, comparing with CG and GG genotype, the CC genotype of rs6496589 has a lower growth amount and rate of waistline and waist height ratio, while the higher-growth measure and velocity of weight index, waistline and waist height ratio of the CC genotype of rs4578621 is higher than CG and GG genotype, even after adjustment for nations, genders and ages. It describes that subjects carrying the CC genotype of rs6496589 or the G allele of rs4578621 are more sensitive to the response of physical exercise in waistline and waist height ratio reducing.Conclusions:1) There was ethnic difference in the BMI distribution with age. We recommended using the BMI cutoff points proposed by the current study to identify overweight and obese children in Urumqi area.2) The PLIN gene in Uygur people is associated with the occurrence of obesity and abdominal obesity. Rs6496589 and rs4578621 in PLIN gene were associated with the change of obesity state under the natural growth and development conditions.3) The effect of intervention by simple health education in short-term was non-significant. The outcome of integrated interventions by health education plus physical activity are effective in a short-term, because they can effectively control the excessive growth of body mass index, and slowdown the degree of obesity in the process.4) There is a certain degree of correlation between PLIN gene polymorphisms and the effect of intervention. Therefore, in order to control and prevent obesity effectively, individualized interventions are recommended.更多还原