基因甲基化与肥胖的关系已引起重视，但人体方面的研究仅有个别国外报道且样本量小。CIDEB、UCP1因与棕色脂肪凋亡、产热有关而受到肥胖研究的关注。课题组致力于人群及实验室相结合的肥胖易感性研究，但发现CIDEB、UCP1基因的部分SNP多态性并不能完全解释肥胖的易感性问题，且明确这些基因存在与甲基化有关的CpG岛。因此本课题拟在已建立的流行病学现场随机抽样进行大样本横断面研究和病例对照研究，检测血白细胞和腹部脂肪组织中CIDEB、UCP1基因甲基化情况，结合前期SNP分析及PRDM16甲基化结果分析它们与肥胖及相关代谢指标的关系及与肥胖相关环境因素的交互作用。课题组通过在中国人群中开展棕色脂肪细胞分化、凋亡、产热相关基因的SNPs和甲基化检测等系列研究，探讨上述基因在肥胖发生的分子流行病学作用及交互作用，对早期发现肥胖易感人群、预防和控制肥胖及相关疾病具有重要意义。

The relationship between gene methylation and obesity has drawn a large amount of attention, but only a few studies have been investigated abroad with a choice of small sample sizes. More and more attentions were paid on CIDEB, UCP1 because of its role in regulation on brown adipocyte apoptosis and thermogenesis. We are engaged in the study of obesity susceptibility based on the field and laboratory research. In our previous research, we found that the SNPs in CIDEB, UCP1 gene couldn't explain the mechanism of obesity completely. There was methylation at CIDEB, UCP1 gene regions. Therefore, a cross-sectional study and a matched case-control study will be carried on in the established epidemiological field through random sampling. The methylation at CIDEB, UCP1 gene in white blood cell and abdominal adipose tissue will be measured. The relationship between associated genes and obesity or related metabolic markers will be further analyzed based on the previous SNPs and methylation of PRDM16 detection. And the interaction between methylation at CIDEB, UCP1 and related environmental factors will be analyzed as well. Our study group try to explore the molecular epidemiological mechanism and interaction of genes associated with differentiation, apoptosis and thermogenesis of brown fat tissue. This study plays a significant role in early detection of obesity susceptible populations, prevention and control of obesity and its related diseases.

背景：中国的肥胖人数已居世界首位，成人体内含有棕色脂肪且具有消耗能量的作用，当其含量相对或绝对不足时，可能会引起肥胖。课题组前期对PRDM16基因的深入研究发现：基因启动子、mRNA及蛋白表达与BMI（超重肥胖）存在一定关联。本研究将针对与棕色脂肪凋亡和产热功能有关的CIDEB和UCP1基因进行深入探索。研究内容：(1) 比较正常体重组和超重/肥胖组CIDEB、UCP1基因启动子甲基化、mRNA水平、蛋白表达量组间的差异；(2) 探索UCP1、PPARGC1A基因单倍型交互作用；(3) 探索SNPs位点发挥致病作用的遗传模型。主要研究结果及关键数据：(1) 超重肥胖组BMI受CIDE-B基因CpG14位点甲基化水平（β=-51.597，P=0.008）影响，回归系数为负，表明甲基化程度越高，CIDEB表达越低，棕色脂肪细胞凋亡越少，产能增加，BMI相应越低。UCP1基因启动子UCP1-2_CpG_10.11.12.13位点与BMI存在回归关系（β=15.370，P=0.004），甲基化程度越高，UCP1表达越少，产热功能降低，BMI越高；(2)仅大网膜脂肪组织中，超重肥胖者CIDE-B基因mRNA的相对表达量是正常组的1.72倍（P=0.019）；UCP1基因的mRNA在组间均无统计学差异；(3) 正常组CIDEB蛋白表达量低于超重肥胖组，尤其是在大网膜组织（P=0.026）。正常组UCP1蛋白表达量与超重肥胖组比较无差异（P>0.05）；(4) PPARGC1A、UCP1两基因存在高度相关，单倍型CTCGAAG可能会增加空腹血糖异常或患糖尿病的风险（OR(95%CI) = 1.745 (1.069 ~ 2.847)），单倍型CTCAAAG可能会降低空腹血糖异常或患糖尿病的发生风险（OR(95%CI) = 0.239 (0.060 ~ 0.958)）；(5) 推导了SNP对定量（BMI）、定性结局（患糖尿病与否）作用的遗传模式，结果发现SNP与慢性疾病关联关系多为加性遗传方式。科学意义：初步探明了CIDE-B、UCP1基因启动子甲基化、mRNA水平、蛋白表达量与BMI（超重肥胖）存在一定的关联；首次尝试了基于单倍型的基因基因交互作用；推导了SNPs对慢性非传染性疾病的遗传作用方式，为肥胖及其相关疾病的遗传学病因的推导提供了新的方法和理论依据。