Genetics of Obesity in Yup'ik Eskimos

肥胖症是一种常见的可预防的发病率和死亡率的原因，少数族裔，独立于 社会经济地位受到不成比例的影响。已知的遗传和环境因素是 在肥胖的发展中很重要，然而基因和基因之间的多态变异之间的相互作用 尽管环境风险因素具有根本性的重要性，但人们对它们知之甚少。我们的初步数据 证明中心体脂在爱斯基摩人中很常见，这是一个“危险”和服务不足的人群 在阿拉斯加西南部。这项修订申请的目的是调查选定的基因是否- 环境的相互作用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，包括一个10 cM的基因组 我们在Yup‘ik Eskimos进行的子扫描：2p、3q、5p、6p、7q、10q、11q、17p和20q。我们一直在寻找 在这些区域发现了生物学上可信的候选基因，并优先选择了7个基因进行穷举遗传 研究：脂联素(3q27)、AMP激酶γ2亚基和核呼吸因子-1(7q36)， 硬脂酰辅酶A去饱和酶(10q23)、固醇调节元件结合蛋白(17p11)、胰岛素敏感葡萄糖 转运蛋白(17p13)和肝细胞核因子4α(20q12)。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，以及几种转录密码 影响脂联素表达的因素。是的，爱斯基摩人传统上吃富含多不饱和脂肪酸的饮食， 非常活跃，但现代化已经导致饮食和活动水平的巨大差异 在个人之间。 我们试图检验这样一种假设，即这些生物学上看似合理的候选基因的多态是 对多不饱和脂肪酸供应减少和体力活动敏感，这些相互作用最终会影响 爱斯基摩人尤皮克人体内脂肪积聚的程度。为达致这个目标，我们的具体目标是： 将我们目前800多个相互关联的爱斯基摩人的数据集扩展到1000个家庭成员； 确定七个候选基因中的SNPs；测试这些基因与肥胖表型的关联； 并测试基因-环境和基因-基因的相互作用。我们方法的优点包括：(1)我们的 持续接触尤皮克·爱斯基摩人，并与其建立出色的研究伙伴关系；(2)大型、明确的 家系；(3)多不饱和脂肪酸摄入量和体力活动水平高度不同。 肥胖症的治疗只取得了一定的成功，也许是因为复杂的病因是 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推动我们的 对肥胖的了解，并将与旨在开发和测试干预措施的未来研究相关， 以及确定肥胖的新治疗靶点。

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.