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The Insulin Gene Variable Number of Tandem Repeat: Associations and Interactions with Childhood Body Fat Mass and Insulin Secretion in Normal Children

Medical Research Council Epidemiology Unit (B.H., K.K.O.), Cambridge CB1 8RN, United Kingdom; Department of Pediatrics (C.J.P., D.B.D., K.K.O.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Unit of Pediatric and Perinatal Epidemiology (ALSPAC study team), Department of Community Based Medicine, University of Bristol, Bristol BS8 1TQ, United Kingdom; and Clinical and Molecular Genetics Unit (M.P.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom

Address all correspondence and requests for reprints to: Dr. Ken Ong, Medical Research Council Epidemiology Unit, Strangeways Research Laboratory, Wort’s Causeway, Cambridge CB1 8RN, United Kingdom. E-mail: ken.ong{at}mrc-epid.cam.ac.uk.

Context: Polymorphism at the insulin gene (INS) variable number of tandem repeat (VNTR) shows variable associations with childhood body mass index (BMI) in different populations.

Objective: The objective of this study was to observe INS VNTR associations with body composition and insulin secretion in children.

Design: The study was designed as a prospective birth cohort study.

Participants: A total of 947 children genotyped for the INS VNTR participated.

Main Outcome Measures: Main outcome measures were whole body dual x-ray emission absorptiometry at 9 yr to estimate height-corrected fat mass index (FMI), truncal FMI, and fat-free mass, and insulin secretion after oral glucose at 8 yr.

Results: Homozygous III/III children had higher BMI (P = 0.020), FMI (P = 0.015), and truncal FMI (P = 0.022) at 9 yr than class I bearers, but no difference in fat-free mass (P = 0.23). Gain in weight SD score between birth and 3 yr was associated positively with BMI, FMI, and truncal FMI in class I bearers, but not in III/III children (p-interaction with genotype = 0.009–0.066). INS VNTR genotype was not associated overall with insulin secretion at 8 yr (P = 0.64), but class I bearers showed a stronger positive correlation between insulin secretion and BMI at 8 yr (regression coefficient ± SE, 0.26 ± 0.05; P < 0.0001) than III/III children (–0.10 ± 0.07; P = 0.48) (p-interaction = 0.003).

Conclusion: We clarified that the overall association between INS VNTR class III/III genotype and larger BMI in this population relates to fat mass, but not fat-free mass. In contrast, among the subgroup of children who showed rapid infancy weight gain, class I bearers tended to have larger BMI and fat mass than III/III children. This genetic interaction could relate to insulin secretion, which, in class I bearers, increased more rapidly with overweight and obesity.

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