Genetics of early childhood obesity and its clinical implications

项目概要/摘要 儿童早期严重肥胖症的发病率不断上升，特别是在代表性不足的少数民族中， 挑战我们年轻人的心脏代谢健康。虽然很大程度上归因于环境，遗传 在决定肥胖方面起着重要作用。这些遗传因素的影响在很大程度上是不确定的， 来自代表性不足的少数民族的儿童，在那里，这种现象的发生率最高。本研究旨在确定 罕见的遗传变异导致大量早发性严重肥胖儿童的严重肥胖 来自不同种族的人主要目标是通过了解肥胖的生物学机制来解释极端肥胖的生物学机制。 遗传变异对导致极度肥胖的生理属性的影响。我们假设 与肥胖相关的遗传变异的负担在患有严重早发性肥胖的儿童中将更高， 受试者样本选自重度肥胖儿童（BMI> 120%95 百分位数，相当于II级肥胖或更高），在6岁以下时记录。我们有 建立了一个大型的多机构合作队列，包括对儿童的前瞻性家庭研究 去波士顿儿童医院的诊所，那里为大量代表性不足的少数民族提供服务， 费城儿童医院的一个队列使用从电子健康记录中提取的数据， 来自生物储存库的样本和来自哥伦比亚大学医学中心的研究队列。为 一项前瞻性家庭研究，邀请严重肥胖儿童及其一级亲属参加， 书房在合作队列中，我们将对患有极端癌症的儿童进行全外显子组测序。 肥胖，体重指数增长最快的轨迹和那些家庭结构有利于 孟德尔遗传模式我们将对大约80个基因进行靶向测序， 那些引起综合征和非综合征形式的肥胖，以及那些在整个外显子组研究中优先考虑的 在所有其他样品中。我们将根据常见的和确定的罕见的基因， 遗传变异，并将其与纵向BMI轨迹和心脏代谢后果相关联 从电子健康记录中提取。此外，我们将进行代谢表型分析，包括 亚组中的能量摄入和消耗、身体组成和对标准餐的激素反应 从遗传风险分数的极端尾部来理解导致严重遗传风险的生理差异。 肥胖 不同遗传祖先的个体可以具有不同的遗传变异模式。可以 研究多个种族可能会发现新的基因。儿童与罕见的变异大的影响，或不同的 遗传风险评分可以帮助描述生理学差异，揭示治疗靶点，或反应 最终影响临床护理的治疗方法。最后，我们的研究队列中， 少数民族将为其他大规模的儿童遗传研究提供一个独特的复制/扩展队列， 严重肥胖。

PROJECT SUMMARY/ABSTRACT The rising prevalence of severe obesity in early childhood, especially in underrepresented minorities, is a challenge to the cardio-metabolic health of our youth. Although largely attributed to the environment, heredity plays a significant role in determining adiposity. The influence of these genetic factors is largely undefined in children from underrepresented minorities where the prevalence is the highest. This study seeks to identify the rare genetic variants contributing to severe obesity in a large cohort of children with severe early onset obesity from mixed ethnic groups. The primary goal is to explain the biology of extreme obesity by understanding the effects of genetic variants on physiological attributes leading to extreme obesity. We hypothesize that the burden of genetic variants related to obesity will be higher in children with severe early onset of obesity, The sample of subjects is selected from children with severe obesity (BMI > 120% of the 95th percentile, equivalent to Class II obesity or higher), documented at an age less than 6 years. We have established a large multi-institutional collaborative cohort including a prospective family study of children attending the clinics at Boston Children’s Hospital that serve large populations of underrepresented minorities, a cohort at Children’s Hospital of Philadelphia using data extraction from the electronic health records and samples from the biorepository and a research cohort from the Columbia University Medical Center. For the prospective family study, children with severe obesity and their first-degree relatives are invited to participate in the study. In the collaborative cohort, we will perform whole exome sequencing in children with extremes of obesity, most rapid trajectory of growth of body mass index and those with family structure favorable for mendelian pattern of inheritance. We will perform targeted sequencing of approximately 80 genes including those causing syndromic and non-syndromic forms of obesity, and those prioritized in the whole exome study in all other samples. We will develop an integrated genetic risk score based on the common and identified rare genetic variants, and correlate it with the longitudinal BMI trajectories and cardio-metabolic consequences extracted from the electronic health records. Additionally, we will perform metabolic phenotyping including energy intake and expenditure, body composition and hormonal response to a standard meal in a subgroup from the extreme tails of the genetic risk scores to understand the differences in physiology leading to severe obesity. Individuals of different genetic ancestries can have different patterns of genetic variation. It is possible that studying multiple ethnicities may identify new genes. Children with rare variants of large effect, or varying genetic risk scores could help describe differences in physiology uncovering therapeutic targets, or a response to treatment that could eventually influence clinical care. Finally, our study cohort of underrepresented minorities will provide a unique replication/extension cohort for other large-scale genetic studies in children with severe obesity.