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Maternal-Fetal Interactions and Birth Order Influence Insulin Variable Number of Tandem Repeats Allele Class Associations with Head Size at Birth and Childhood Weight Gain

¹ Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K.
² Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K.
³ Avon Longitudinal Study of Parents and Children, University of Bristol, Bristol, U.K.
⁴ Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, U.K.

Polymorphism of the insulin gene (INS) variable number of tandem repeats (VNTR; class I or class III alleles) locus has been associated with adult diseases and with birth size. Therefore, this variant is a potential contributory factor to the reported fetal origins of adult disease. In the population-based Avon Longitudinal Study of Pregnancy and Childhood birth cohort, we have confirmed in the present study the association between the INS VNTR III/III genotype and larger head circumference at birth (odds ratio [OR] 1.92, 95% CI 1.23–3.07; P = 0.004) and identified an association with higher cord blood IGF-II levels (P = 0.05 to 0.0001). The genotype association with head circumference was influenced by maternal parity (birth order): the III/III OR for larger head circumference was stronger in second and subsequent pregnancies (OR 5.0, 95% CI 2.2–11.5; P = 0.00003) than in first pregnancies (1.2, 0.6–2.2; P = 0.8; interaction with birth order, P = 0.02). During childhood, the III/III genotype remained associated with larger head circumference (P = 0.004) and was also associated with greater BMI (P = 0.03), waist circumference (P = 0.03), and higher fasting insulin levels in girls (P = 0.02). In addition, there were interactions between INS VNTR genotype and early postnatal weight gain in determining childhood BMI (P = 0.001 for interaction), weight (P = 0.005), and waist circumference (P = 0.0005), such that in the 25% of children (n = 286) with rapid early postnatal weight gain, class III genotype–negative children among this group gained weight more rapidly. Our results indicate that complex prenatal and postnatal gene–maternal/fetal interactions influence size at birth and childhood risk factors for adult disease.

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