The rising prevalence of severe obesity in early childhood, especially in underrepresented minorities, is achallenge to the cardio-metabolic health of our youth. Although largely attributed to the environment, heredityplays a significant role in determining adiposity. The influence of these genetic factors is largely undefined inchildren from underrepresented minorities where the prevalence is the highest. This study seeks to identify therare genetic variants contributing to severe obesity in a large cohort of children with severe early onset obesityfrom mixed ethnic groups. The primary goal is to explain the biology of extreme obesity by understanding theeffects of genetic variants on physiological attributes leading to extreme obesity. We hypothesize that theburden 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 95thpercentile, equivalent to Class II obesity or higher), documented at an age less than 6 years. We haveestablished a large multi-institutional collaborative cohort including a prospective family study of childrenattending 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 andsamples from the biorepository and a research cohort from the Columbia University Medical Center. For theprospective family study, children with severe obesity and their first-degree relatives are invited to participate inthe study. In the collaborative cohort, we will perform whole exome sequencing in children with extremes ofobesity, most rapid trajectory of growth of body mass index and those with family structure favorable formendelian pattern of inheritance. We will perform targeted sequencing of approximately 80 genes includingthose causing syndromic and non-syndromic forms of obesity, and those prioritized in the whole exome studyin all other samples. We will develop an integrated genetic risk score based on the common and identified raregenetic variants, and correlate it with the longitudinal BMI trajectories and cardio-metabolic consequencesextracted from the electronic health records. Additionally, we will perform metabolic phenotyping includingenergy intake and expenditure, body composition and hormonal response to a standard meal in a subgroupfrom the extreme tails of the genetic risk scores to understand the differences in physiology leading to severeobesity. Individuals of different genetic ancestries can have different patterns of genetic variation. It is possiblethat studying multiple ethnicities may identify new genes. Children with rare variants of large effect, or varyinggenetic risk scores could help describe differences in physiology uncovering therapeutic targets, or a responseto treatment that could eventually influence clinical care. Finally, our study cohort of underrepresentedminorities will provide a unique replication/extension cohort for other large-scale genetic studies in children withsevere obesity.

Public Health Relevance

Severe obesity is a serious threat to our nation's health. Besides environment; heredity is known to contributeto obesity; although the effects of these genetic factors is not well known; especially in underrepresentedminorities. This study proposes to understand the role of genetic causes that influence severe obesity in earlychildhood and understand their effect on clinical presentation with a goal to identify better treatment andprevention.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Digestive Diseases and Nutrition C Subcommittee (DDK-C)
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Saslowsky, David E
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Thaker, Vidhu; Carter, Ben; Putman, Melissa (2018) Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database Syst Rev 12:CD008901
Thaker, Vidhu V (2017) GENETIC AND EPIGENETIC CAUSES OF OBESITY. Adolesc Med State Art Rev 28:379-405