Genetics of early childhood obesity and its clinical implications

项目摘要/摘要 儿童早期严重肥胖的患病率不断上升，特别是在代表性不足的少数民族中，这是一个 对我们年轻人的心脏代谢健康的挑战。尽管很大程度上归因于环境，但遗传 在确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没有定义 来自流行率最高的代表性不足的少数族裔的儿童。这项研究试图找出 在一大批重度早发性肥胖儿童中导致严重肥胖的罕见基因变异 来自混合种族的人。其主要目标是通过了解极端肥胖的生物学机制 基因变异对导致极端肥胖的生理属性的影响。我们假设 与肥胖相关的基因变异的负担在严重早发肥胖的儿童中会更高， 受试者样本选自严重肥胖儿童(BMI&GT；占第95名的120% 百分位数，相当于II级肥胖或更高)，记录在案的年龄在6岁以下。我们有 建立了一个大型多机构协作队列，包括一项关于儿童的预期家庭研究 参加波士顿儿童医院的诊所，这些诊所为大量未被充分代表的少数民族提供服务， 费城儿童医院的一群人使用从电子健康记录和 来自生物仓库的样本和来自哥伦比亚大学医学中心的研究队列。对于 未来家庭研究，严重肥胖儿童及其一级亲属被邀请参加 这项研究。在协作队列中，我们将对患有极端疾病的儿童进行完整的外显子测序 肥胖，体重指数增长最快的轨迹和家庭结构有利于 孟德尔式的继承模式。我们将对大约80个基因进行定向测序，包括 引起症状性和非症状性肥胖的人，以及在整个exome研究中优先考虑的人 在所有其他样本中。我们将根据常见的和已识别的罕见疾病开发综合遗传风险评分 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，我们还将进行代谢表型鉴定，包括 亚组中标准膳食的能量摄入和消耗、身体成分和荷尔蒙反应 从极端尾部的遗传风险分数来理解生理差异导致的严重 肥胖。 不同遗传祖先的个体可能有不同的遗传变异模式。这是有可能的 研究多个种族可能会发现新的基因。儿童罕见变异效应大，或变异大 遗传风险分数可以帮助描述发现治疗靶点或反应的生理学差异 最终可能会影响临床护理的治疗。最后，我们研究的代表不足的队列 少数族裔将为其他大规模的儿童遗传学研究提供独特的复制/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.