GENETIC EPIDEMILOGY OF ENGERGY METABOLISM IN BLACK GIRLS

描述：非裔美国人（AA）女性肥胖的高患病率是 公共卫生的重要性，因为AA妇女遭受更高的死亡率， 心血管和肾脏疾病的患病率高于白色女性。他们的原因 对肥胖的显著易感性仍然知之甚少，尽管现在 已知AA女性表现出较低的静息能量消耗（REE）比W 妇女我们提出了一个多管齐下的代谢和遗传流行病学研究， 检测与能量代谢有关的两个候选基因（UCP 3和b3 AR） 在这一高危人群中尚待研究。本申请 建立在我们先前对150名双胞胎队列研究的结果基础上， 19-21岁的年轻女性。我们发现REE（调整脂肪量和无脂肪） 在整个研究期间，AA女性的体重）始终低于W约78千卡/天。 肥胖症的所有症状此外，那些AA妇女纯合子REE较低， UCP 3的C等位基因（外显子5）。然而，由于C的相对稀有性， AA中的等位基因，我们的样本量为5个AA纯合子的C等位基因只产生了一个 弱关联，p=0.05。我们建议筛选600名AA女孩，年龄在12-15岁， 使用口腔拭子作为获得DNA的非侵入性方法，以确定 UCP 3基因型和b3 AR基因型。我们将招募211名女孩， 根据他们的UCP 3基因型选择，用于测量REE和身体 组合物（使用DEXA）在临床研究的受控环境中 辛辛那提儿童医院的中心。我们将研究稀土元素的变化 在UCP 3的基因型之间进行了大样本研究，以证实我们之前的研究结果。 发现拟议的2x 3设计将使我们能够检查是否影响 与UCP 3变异相关的突变是由于UCP 3基因座单独或由于UCP 3基因座的突变。 UCP 3和b3 AR之间的加性效应或相互作用。这还没有得到 以前考虑过。我们的研究将有助于更好地了解 两个重要的能量代谢候选基因UCP 3 和b3 AR，以及在这个非常高的REE水平的个体间差异， 肥胖风险人群。此应用程序还建立在 PI和研究人员之间建立良好的合作关系 在辛辛那提儿童医院和法雷尔博士的人类 匹兹堡大学遗传学实验室。因此，获得的信息 从拟议的研究应该增加我们对复杂的理解 种族、遗传、能量代谢和肥胖之间的相互关系 发展反过来，这应该有助于推进我们对“节俭”基因的探索， 由于能量消耗的吝啬可能是主要的表型表现， 这样的基因型。

DESCRIPTION: The high prevalence of obesity in African-American (AA) women is of public health importance since AA women suffer higher mortality from cardiovascular and renal diseases than do white (W) women. The reason for their marked susceptibility to obesity remains poorly understood though it is now known that AA women manifest lower resting energy expenditure (REE) than W women. We propose a multi-pronged metabolic and genetic epidemiologic study to examine two candidate genes (UCP3 and b3AR) implicated in energy metabolism which have yet to be investigated in this high risk group. This application builds upon the findings from our previous study of a biracial cohort of 150 young women aged 19-21. We showed that REE (adjusted for fat mass and fat-free mass) in AA women was consistently lower than W by about 78 kcal/day across the entire range of adiposity. Further, REE was lower for those AA women homozygous for the C allele of UCP3 (exon 5). However, due to the relative rarity of the C allele among AA, our sample size of 5 AA homozygous for C allele yielded only a weak association, p=0.05. We propose to screen 600 AA girls, aged 12-15 years, using buccal swabs as a non-invasive method of obtaining DNA, to determine their UCP3 genotypes as well as b3AR genotypes. We will recruit 211 girls, selected based on their UCP3 genotype, for measurements of REE and body composition (using DEXA) in a controlled setting of the Clinical Research Center at the Cincinnati Children's Hospital. We will examine variation in REE across the genotypes of UCP3 with a large sample to corroborate our previous finding. The proposed 2x3 design will allow us to examine whether the effects associated with UCP3 variation are due to the UCP3 locus alone or due to the additive effect or interaction between UCP3 and b3AR. This has not been considered before. Our study will help to better understand the relationship between variation in two important candidate genes for energy metabolism, UCP3 and b3AR, and inter-individual variation in the levels of REE in this very high risk (for obesity) population. This application also builds on a well-established collaborative relationship between the PI and the researchers at the Cincinnati Children's Hospital and also with Dr. Ferrell's Human Genetics Laboratory at the University of Pittsburgh. Thus, information obtained from the proposed study should increase our understanding of the complex interrelationship between ethnicity, genetics, energy metabolism, and obesity development. This, in turn, should help advance our quest for "thrifty" genes, since parsimonious energy expenditure may be the main phenotypic manifestation of such a genotype.