Association of Genomic Predictors of Body Fat Amount and Distribution and of tti

项目总结（见说明）; 了解肥胖和癌症之间的复杂关系是一个科学优先事项，在减少这两种常见慢性病的广泛负担方面具有重大的公共卫生意义。项目2的目标是：（1）确定影响高危肥胖表型的遗传变异;（2）揭示宿主基因、肠道微生物群和肥胖之间的关系;（3）确定遗传祖先和肥胖表型之间的关联，为所有四个项目提供有效的种族/民族生物学测量;以及 (d)有助于阐明与肥胖、乳腺癌和结肠直肠癌最相关的关键暴露预测因素。我们在目标1中建议进行体脂分布的全基因组关联研究（GWAS）。 具体来说，我们将对2,000名多种族队列参与者中超过430万个单核苷酸多态性进行基因分型，这是所有四个项目的共同点，他们将通过全身双能X射线吸收测定法和腹部磁共振成像进行身体成分评估。接下来在目标2中，我们将对肠道微生物群的相对丰度进行全基因组关联研究，更具体地说，与肥胖相关的肠道微生物谱。在这里，我们将联合收割机的基因分型数据从2,000 MEC受试者检查目标1与现有的GWAS数据从超过4,200 MEC参与者。对于这6,200名受试者，我们将在项目4中通过粪便样本的16 S基因rRNA测序来表征肠道微生物群的结构。 据我们所知，这将是第一次大规模全面调查宿主遗传学和肠道微生物群落之间的关系，特别是与肥胖相关的肠道微生物谱。最后，我们的最终目标是将项目2的遗传结果与其他项目的遗传结果相结合，以研究相互关系 跨数据维度（饮食、生活方式/行为、生化和激素因素、代谢物和肠道微生物组成），构建体脂量和分布的最佳预测模型，并探索预测值与乳腺癌和结直肠癌风险的关系。最后一个目标将包括测试肥胖表型和肠道微生物组成与乳腺癌和结直肠癌易感性的风险变体。 关联检验将在我们的多种族队列中嵌套的乳腺癌（3，243例，3，243例对照）和结直肠癌（2，588例，2，588例对照）的大型病例对照研究中进行。这项建议的优点包括：1）研究的创新性; 2）多学科研究团队; 3）有效利用现有资源; 4）肥胖和癌症的科学和公共卫生意义。知识 这项研究获得的结果可能会大大促进我们对驱动体脂分布的生物学因素及其对几个种族/民族人群中常见癌症发展的影响的理解。

PROJECT SUMMARY (See instructions); Understanding the complex relationship between obesity and cancer is a scientific priority with significant public health implications in reducing the wide-spread burden of these two common chronic diseases. The goals of Project 2 are to: (1) identify genetic variants that influence high-risk obesity phenotypes; (2) uncover the relationship between host genes, gut microbiota, and obesity; (3) determine the association between genetic ancestry and obesity phenotypes, usefully providing a biological measure of race/ethnicity to all four projects; and (d) help shed light on the key exposure predictors that are most relevant for obesity, breast and colorectal cancers. We propose in Aim 1 to conduct a genome-wide association study (GWAS) of body fat distribution. Specifically, we will genotype over 4.3 million single nucleotide polymorphisms in 2,000 Multiethnic Cohort participants, common to all four projects, who will undergo body composition assessment by whole-body dual energy X-ray absorptiometry and abdominal magnetic resonance imaging. Next in Aim 2, we will conduct a genome-wide association study of the relative abundance of the gut microbiota and, more specifically, the gut microbial profiles associated with obesity. Here we will combine genotyping data from the 2,000 MEC subjects examined in Aim 1 with existing GWAS data from over 4,200 MEC participants. For these 6,200 subjects, we will characterize the architecture of the gut microbiota by 16S gene rRNA sequencing of stool samples in Project 4. To our knowledge, this will be the first large-scale comprehensive investigation of the relationship between host genetics and the gut microbial community, and in particular gut microbial profiles associated with obesity. Lastly, our final aim will integrate genetic results from Project 2 with those from the other projects to study the interrelationships across data dimensions (diet, lifestyle/behaviors, biochemical and hormonal factors, metabolites, and gut microbial composition), construct best predictive models of body fat amount and distribution, and explore the relation of the predicted values with breast and colorectal cancer risks. This last aim will include testing risk variants for obesity phenotypes and gut microbial composition with breast and colorectal cancer susceptibility. Association testing will be conducted in our large case-control studies of breast (3,243 cases, 3,243 controls) and colorectal (2,588 cases, 2,588 controls) cancer nested within the Multiethnic Cohort. The strengths of this proposal include: 1) the innovativeness of the research; 2) the multi-disciplinary investigative team, 3) the efficient use of existing resources and 4) the scientific and public health significance of obesity and cancer. The knowledge gained by this study may significantly advance our understanding of the biological factors driving body fat distribution and their effects on the development of common cancers among several racial/ethnic populations.