Genetics of early childhood obesity and its clinical implications

儿童早期肥胖的遗传学及其临床意义

• 批准号: 10013209
• 负责人: Vidhu V. Thaker
• 金额: $ 18.33万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-29 至 2023-03-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013209
• 关键词: 6 year old; Academic Medical Centers; African American; Age; Agonist; Alleles; American; Behavior Therapy; Biochemical; Biological; Biology; Body Composition; Body mass index; Boston; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Child; Clinic; Clinical; Cohort Studies; Collaborations; Data; Disease; Electronic Health Record; Energy Intake; Energy Metabolism; Environment; Epidemic; Ethnic Origin; Ethnic group; European; Exons; Family Study; Fatty acid glycerol esters; First Degree Relative; Frequencies; Future; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Growth; Health; Heart Diseases; Heredity; High-Throughput Nucleotide Sequencing; Hormonal; Human Genetics; Individual; Inheritance Patterns; Institution; LEPR gene; Leptin; Life Style; Low-Density Lipoproteins; Metabolic; Morbid Obesity; Mutation; NTRK2 gene; Neuraxis; Obesity; Outcome; Pathway interactions; Pattern; Pediatric Hospitals; Phenotype; Philadelphia; Physiological; Physiology; Play; Population; Prader-Willi Syndrome; Prevalence; Prevention; Recombinants; Regulation; Research; Rest; Role; Sampling; Stratification; Structure; Subgroup; Syndrome; Tail; Testing; Underrepresented Minority; Underrepresented Populations; Variant; Weight; Weight Gain; Youth; adult obesity; base; biobank; cardiometabolism; causal variant; clinical care; cohort; early childhood; exome; exome sequencing; family structure; feeding; genetic variant; genome wide association study; genome-wide; insight; loss of function; metabolic phenotype; metabolic profile; mutation carrier; neurobehavioral disorder; new therapeutic target; novel; obesity in children; prevent; prospective; rare variant; response; screening; severe early onset obesity; targeted sequencing; therapeutic target; treatment response

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.

项目摘要/摘要 童年时期严重肥胖的患病率上升，尤其是代表性不足的少数群体，是一个 挑战我们年轻人的心替代人健康。虽然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不确定 来自人数不足的少数民族的儿童，患病率最高。这项研究旨在确定 罕见的遗传变异在大量患有严重早期发作的儿童中导致严重肥胖症 来自混合种族。主要目标是通过了解 遗传变异对物理属性导致极端肥胖的影响。我们假设 严重早期发作的儿童，与肥胖有关的遗传变异负担将更高， 受试者的样本是从严重肥胖儿童中选择的（BMI>第95位的120％ 百分位数，相当于II类对象或更高），记录在不到6岁的年龄。我们有 建立了一个大型的多机构合作群体，包括对儿童的前瞻性家庭研究 参加波士顿儿童医院的诊所，为大量人群不足的少数民族提供服务， 费城儿童医院的队列使用电子健康记录中的数据提取， 来自Biorepository的样本和哥伦比亚大学医学中心的研究队列。为了 前瞻性家庭研究，邀请患有严重肥胖的儿童及其一级亲戚参加 研究。在协作人群中，我们将在极端的儿童中进行整个外显子组测序 肥胖，体重指数生长的最快轨迹以及有利于家庭结构的人 孟德尔的继承模式。我们将执行大约80个基因的目标测序 那些引起肥胖的综合症和非综合性形式的人，以及整个外显型研究中的优先级 在所有其他样品中。我们将基于共同的综合遗传风险评分，并确定为罕见 遗传变异，并将其与纵向BMI轨迹和心脏代谢后果相关 从电子健康记录中提取。此外，我们将进行代谢表型，包括 能量摄入和支出，身体成分和对标准餐的响应 从遗传风险评分的极端尾巴，以了解​​生理学的差异导致严重 肥胖。 不同遗传祖先的个体可以具有不同的遗传变异模式。可能 研究多种种族可以鉴定新基因。具有较大效果的稀有变体或不同的儿童 遗传风险评分可以帮助描述生理学的差异，从而发现治疗靶点或反应 治疗最终可能影响临床护理。最后，我们的研究人数不足 少数民族将为患有其他大规模遗传研究提供独特的复制/扩展队列 严重的肥胖。