Interaction between early environment and genetic predisposition instigates the metabolically obese, normal weight phenotype in children: findings from the BCAMS study

in European Journal of Endocrinology
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  • 1 Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
  • 2 Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
  • 3 Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana, USA
  • 4 Department of Endocrinology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 5 Department of Epidemiology, Capital Institute of Paediatrics, Beijing, China
  • 6 Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

Correspondence should be addressed to M Li; Email:
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A subset of normal-weight individuals appears predisposed to obesity-related cardiometabolic abnormalities. Studies of this metabolically obese, normal weight (MONW) phenotype in youth are scarce. We aimed to identify early environmental and genetic factors associated with MONW in children.


Overall, 1475 normal-weight Chinese children aged 6–18 were recruited from the Beijing Children and Adolescents Metabolic Syndrome study cohort. Birthweight, childhood lifestyle, socio-economic factors, and 20 genetic variants previously shown to be associated with BMI or glucose metabolism in East Asian adults were examined for their association with the MONW phenotype. MONW was defined by exhibiting any metabolic syndrome component.


After adjusting for covariates including BMI, low birthweight and low levels of physical activity, fruit consumption, parental education and household income, as well as CDKAL1 rs2206734 genotype were independent predictors of the MONW phenotype (all P < 0.05). Moreover, rs2206734 interacted with birthweight to predict the MONW phenotype (Pinteraction = 0.0008). Among high (>75th percentile) birthweight individuals, each C allele at this locus was associated with a 62% reduced risk of MONW (OR = 0.38; 95% CI = 0.26-0.58; P = 5.71 × 10−6), while no such genetic associations were found in intermediate or low birthweight individuals (P > 0.1). This CDKAL1-MONW relationship in high birthweight individuals was especially strong in the presence of favorable childhood environmental factors (high levels of physical activity, fruit consumption, parental education and household income) (Pinteraction = 0.013).


Our findings provided the novel evidence that early environment (especially birthweight) and genetics, along with their interaction with one another, play important roles in predicting the MONW phenotype among children.

Supplementary Materials

    • Supplemental Table 1. Associations of the 20 candidate SNPs with MONW among children and adolescents
    • Supplemental Figure 1. Flow chart of the cohort


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