Genetic Determinants of Taste Preferences and Risk of Metabolic Disease

描述(申请人提供)：肥胖和2型糖尿病(T2D)是日益严重的公共卫生问题。虽然饮食是这些疾病发生的一个众所周知的因素，但公共卫生在改变饮食行为方面的努力取得的成功有限。苦的，甜的 而咸味偏好是饮食摄入量的重要决定因素。味觉也可能具有直接影响新陈代谢健康的功能。因此，特定的口味偏好可能会影响肥胖和T2D的风险，但支持这一概念的人类证据有限。在人群研究中，很少考虑口味偏好的个体间差异。了解这种变异的遗传决定因素对于加深我们对味道生物学的理解以及阐明对苦味、甜味或咸味食物的偏好在代谢性疾病发展中可能起到的作用特别有用。这些知识还可用于设计更有效的干预措施，以预防和治疗这些疾病。此前旨在确定味觉遗传基因的研究采取了从生物学到行为的方法来发现基因。随着遗传领域的进步和大样本的出现，一种强大的、不可知论的方法现在成为可能。然而，在大规模的基于人群的研究中，口味偏好并不是通常被衡量的，因此限制了对这些特征的传统和遗传流行病学研究。这项提议的第一个目标是开发可以从现有的食物偏好或消费数据中得出的口味偏好分数。我们的第二个目标是确定与人类味觉偏好相关的遗传位点，然后应用这一分子知识来破译味觉偏好在肥胖和T2D发育中所起的作用。我们将使用从食物消费数据和现有的全基因组扫描构建的口味偏好分数，这些扫描来自基于人群的队列：护士健康研究、卫生专业人员跟踪研究和女性基因组健康研究。我们将复制Charge联盟中最有希望的基因座，然后使用GIGNAL和CATURE的现有结果来研究它们对肥胖和T2D风险的影响；大型联盟分别致力于人体测量和T2D的遗传学研究。通过结合先进的遗传知识和技术、先进的统计工具、定义明确的特征和足够大的样本，我们的研究将为控制人类口味偏好的因素及其对肥胖和T2D发展的影响提供新的见解。拟议的研究计划与NIDCD的嗅觉和味觉计划的优先顺序I和优先顺序III一致：我们试图了解味觉偏好的“正常”变化，以及这种变化如何在种群水平上影响代谢性疾病。此外，这项研究的结果将为减少饮食相关疾病的风险以及开发治疗和预防的新的行为和药理学途径开辟新的研究路线，从而间接解决该计划的第四个优先领域。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes (T2D) are growing public health concerns. Although diet is a well-known factor in the development of these conditions, public health efforts in dietary behavior modification have met with limited success. Bitter, sweet and salty taste preferences are important determinants of dietary intake. Taste may also serve functions that may directly impact metabolic health. Specific taste preferences might therefore impact risk of obesity and T2D, but human evidence supporting this notion is limited. Inter-individual variability in taste- preferences is rarely considered in population studies. Knowledge of the genetic determinants of this variation can be especially useful in furthering our understanding of taste biology and to elucidate the role that preferences for bitter, sweet, or salty foods may have in metabolic disease development. Such knowledge can also be used in designing more effective interventions for the prevention and treatment of these conditions. Previous studies aimed to identify taste genetic loci have taken a biology-to-behavior approach to gene discovery. A powerful, agnostic approach is now possible with advancements in the genetic field and the availability of large sample sizes. Taste preferences, however, are not commonly measured in large population-based studies; thus limiting both traditional and genetic epidemiological studies of these traits. The first goal of this proposal is to develop taste preference scores that can be derived from existing food preference or consumption data. Our second goal is to identify genetic loci associated with human taste preferences and then to apply this molecular knowledge to deciphering the role taste preferences play in obesity and T2D development. We will use taste preference scores constructed from food consumption data and existing genome-wide scans available from population-based cohorts: the Nurses' Health Study, Health Professionals Follow-up Study and the Women's Genome Health Study. We will replicate the most promising loci in the CHARGE consortium and then examine their impact on obesity and T2D risk using available results from GIANT and DIAGRAM; large consortia committed to the genetic study of anthropometry and T2D, respectively. By combining advanced genetic knowledge and technology, sophisticated statistical tools, a well-defined trait and a sufficiently sized sample, our research will provide novel insight into factors governing human taste preferences and the impact they have on obesity and T2D development. The proposed research plan aligns with Priorities I and III of NIDCD's Smell and Taste program: we seek to understand 'normal' variation in taste preference and how this variation impacts metabolic disease at a population level. Moreover, results of this study will foster new lines of investigatin for reducing risk of diet-related conditions and for developing novel behavioral and pharmacological avenues of treatment and prevention and thus indirectly addresses the program's fourth priority area.