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: 10445160
• 负责人: Vidhu V. Thaker
• 金额: $ 9.16万
• 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/10445160
• 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; excessive weight gain; exome; exome sequencing; family structure; feeding; genetic variant; genome wide association study; genome-wide; insight; loss of function; metabolic phenotype; metabolic profile; multi-ethnic; 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.

项目概要/摘要 幼儿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群体中，这是一个 对我们年轻人心脏代谢健康的挑战虽然很大程度上归因于环境、遗传。 这些遗传因素的影响在很大程度上尚不清楚。 本研究旨在确定患病率最高的代表性不足的少数群体的儿童。 罕见的基因变异导致大量早发性严重肥胖儿童的严重肥胖 来自混合种族群体的主要目标是通过了解极端肥胖的生物学原理。 遗传变异对生理属性的影响导致极度肥胖。 严重早发性肥胖的儿童中与肥胖相关的遗传变异负担会更高， 受试者样本选自重度肥胖儿童（BMI>95%的120%） 百分位（相当于 II 级肥胖或更高），记录年龄小于 6 岁。 建立了一个大型的多机构合作队列，包括一项儿童前瞻性家庭研究 去波士顿儿童医院的诊所就诊，该医院为大量代表性不足的少数族裔提供服务， 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， 来自生物样本库和哥伦比亚大学医学中心的研究队列的样本。 前瞻性家庭研究，邀请重度肥胖儿童及其一级亲属参加 在该研究中，我们将对患有极端疾病的儿童进行全外显子组测序。 肥胖、体重指数增长最快的人群以及家庭结构有利的人群 我们将对大约 80 个基因进行靶向测序，其中包括孟德尔遗传模式。 导致综合征和非综合征形式肥胖的因素，以及整个外显子组研究中优先考虑的因素 在所有其他样本中，我们将根据常见和已识别的罕见样本制定综合遗传风险评分。 遗传变异，并将其与纵向 BMI 轨迹和心脏代谢后果相关联 此外，我们将进行代谢表型分析，包括。 亚组中标准膳食的能量摄入和消耗、身体成分和激素反应 从遗传风险评分的极端尾部了解导致严重疾病的生理学差异 肥胖。 不同遗传祖先的个体可能有不同的遗传变异模式。 研究多个种族可能会发现具有大影响的罕见变异或变化的新基因。 遗传风险评分可以帮助描述生理学差异，揭示治疗目标或反应 最后，我们的研究队列中代表性不足。 少数族裔将为其他大规模儿童遗传研究提供独特的复制/扩展队列 严重肥胖。

项目成果

Metabolite signature of diabetes remission in individuals with obesity undergoing weight loss interventions.

接受减肥干预的肥胖患者糖尿病缓解的代谢特征。

• 发表时间: 2024-02
• 作者: Thaker, Vidhu V;Kwee, Lydia Coulter;Chen, Haiying;Bahnson, Judy;Ilkayeva, Olga;Muehlbauer, Michael J;Wolfe, Bruce;Purnell, Jonathan Q;Pi;Newgard, Christopher B;Shah, Svati H;Laferrère, Blandine;Look AHEAD Research Group
• 通讯作者: Look AHEAD Research Group

Psychosocial, behavioral and clinical correlates of children with overweight and obesity.

超重和肥胖儿童的心理社会、行为和临床相关性。

• 发表时间: 2020-06-10
• 影响因子: 2.4
• 作者: Thaker, Vidhu V;Osganian, Stavroula K;deFerranti, Sarah D;Sonneville, Kendrin R;Cheng, Jennifer K;Feldman, Henry A;Richmond, Tracy K
• 通讯作者: Richmond, Tracy K

Exploring Genetic Testing for Rare Disorders of Obesity: Experience and Perspectives of Pediatric Weight Management Providers.

探索罕见肥胖症的基因检测：儿科体重管理提供者的经验和观点。

• 发表时间: 2024-01-08
• 作者: Roberts, Karyn J;Chaves, Eileen;Ariza, Adolfo J;Thaker, Vidhu V;Cho, Chi C;Binns, Helen J
• 通讯作者: Binns, Helen J

Recombinant growth hormone therapy for cystic fibrosis in children and young adults.

重组生长激素治疗儿童和年轻人囊性纤维化。

• 发表时间: 2018
• 作者: Thaker, Vidhu;Carter, Ben;Putman, Melissa
• 通讯作者: Putman, Melissa

Recombinant growth hormone therapy for cystic fibrosis in children and young adults.

重组生长激素治疗儿童和年轻人囊性纤维化。

• 发表时间: 2021-08-23
• 作者: Thaker, Vidhu;Carter, Ben;Putman, Melissa
• 通讯作者: Putman, Melissa