Genetics of Obesity in Yup'ik Eskimos

描述（由申请人提供）：肥胖是一种常见的可预防的发病率和死亡率的原因，少数民族，独立于社会经济地位，受到不成比例的影响。已知遗传和环境因素在肥胖症的发展中是重要的，然而，尽管基因内的多态性变体和环境风险因素之间的相互作用非常重要，但人们对它们的了解却很少。我们的初步数据表明，中心体脂肪在Yup'ik爱斯基摩人中很常见，Yup' ik爱斯基摩人是阿拉斯加西南部的一个“危险”和服务不足的人群。本修订申请的目的是调查选定的基因-环境相互作用是否是爱斯基摩人肥胖的危险因素。肥胖基因组连锁扫描在多项独立研究中涉及以下染色体区域，包括我们在Yup'ik Eskimos中进行的10 cM基因组亚扫描：2 p，3q，5 p，6p，7 q，10 q，11 q，17 p和20 q。我们在这些区域寻找生物学上合理的候选基因，并优先考虑7个基因进行详尽的遗传研究：脂联素（3q 27），AMP激酶γ 2亚基和核呼吸因子-1（7 q36），硬脂酰CoA去饱和酶（10 q23），甾醇调节元件结合蛋白（17 p11），胰岛素敏感性葡萄糖转运蛋白（17 p13），和肝细胞核因子4 α（20 q12）。这些基因及其编码的蛋白质受多不饱和脂肪酸（PUFAs）和体力活动的调节，并且几个编码参与脂联素表达的转录因子。爱斯基摩人的饮食传统上富含多不饱和脂肪酸，并且非常活跃，但现代化导致了个体之间饮食和活动水平的巨大差异。我们试图验证这一假设，即这些生物学上合理的候选基因的多态性对PUFA可用性和体力活动的减少敏感，并且这些相互作用最终影响Yup'ik爱斯基摩人体内脂肪积累的程度。为了实现这一目标，我们的具体目标是：将我们现有的800多个相互关联的Yup'ik爱斯基摩人的数据集扩展到1000个家庭成员;彻底确定7个候选基因中的SNP;测试这些基因与肥胖表型的相关性;并测试基因-环境和基因-基因相互作用。我们方法的优势包括：（1）我们与Yup'ik Eskimos的持续接触和良好的研究伙伴关系;（2）大型明确的谱系;（3）PUFA摄入量和身体活动的高度可变水平。肥胖症的治疗仅取得了一定的成功，可能是因为复杂的病因在很大程度上是未知的。从这项研究中获得的基因-环境相互作用的发现将进一步加深我们对肥胖的理解，并将与未来旨在开发和测试干预措施以及确定肥胖新治疗靶点的研究相关。

DESCRIPTION (provided by applicant): Obesity is a common preventable cause of morbidity and mortality, and ethnic minorities, independent of socioeconomic status, are disproportionately affected. Genetic and environmental factors are known to be important in the development of obesity, yet the interactions between polymorphic variants within genes and environmental risk factors are poorly understood despite their fundamental importance. Our preliminary data demonstrate that central body fat is common among Yup'ik Eskimos, an "at risk" and underserved population in Southwest Alaska. The objective of this revised application is to investigate whether selected gene- environment interactions are risk factors for obesity in Yup'ik Eskimos. Obesity genome linkage scans have implicated the following chromosomal regions in multiple independent studies, including a 10cM genome sub-scan we conducted in Yup'ik Eskimos: 2p, 3q, 5p, 6p, 7q, 10q, 11q, 17p and 20q. We searched for biologically plausible candidate genes in these regions and prioritized seven genes for exhaustive genetic investigation: adiponectin (3q27), AMP kinase gamma 2 subunit and nuclear respiratory factor-1 (7q36), stearoyl CoA desaturase (10q23), sterol regulatory element binding protein (17p11), insulin sensitive glucose transporter (17p13), and hepatocyte nuclear factor 4 alpha (20q12). These genes and their encoded proteins are regulated by polyunsaturated fatty acids (PUFAs) and physical activity, and several code for transcription factors involved in adiponectin expression. Yup'ik Eskimos have traditionally eaten a diet rich in PUFAs, and were extremely active, but modernization has resulted in dramatic differences in diet and activity levels among individuals. We seek to test the hypothesis that polymorphisms in these biologically plausible candidate genes are sensitive to reduced PUFA availability and physical activity, and that these interactions ultimately influence the degree of body fat accumulation in Yup'ik Eskimos. To achieve this objective, our specific aims are: to extend our current data set of over 800 interrelated Yup'ik Eskimos to 1000 family members; to exhaustively identify SNPs in the seven candidate genes; to test these genes for association with obesity phenotypes; and to test for gene-environment and gene-gene interactions. Strengths of our approach include: (1) our ongoing access to, and excellent research partnership with, Yup'ik Eskimos; (2) large well-defined pedigrees; and (3) highly variable levels of PUFA intake and physical activity. Treatment for obesity has been only modestly successful, perhaps because the complex etiology is largely unknown. The discovery of gene-environment interactions gained from this study will further our understanding of obesity and will be relevant to future studies aimed at developing and testing interventions, and identifying novel therapeutic targets for obesity.