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
- Ken K. Ong1,
- Clive J. Petry1,
- Bryan J. Barratt2,
- Susan Ring3,
- Heather J. Cordell2,
- Diane L. Wingate1,
- the Avon Longitudinal Study of Pregnancy and Childhood Study Team3,
- Marcus E. Pembrey4,
- John A. Todd2 and
- David B. Dunger1
- 1Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K.
- 2Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K.
- 3Avon Longitudinal Study of Parents and Children, University of Bristol, Bristol, U.K.
- 4Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, U.K.
- Address correspondence and reprint requests to Prof. David B. Dunger, Department of Pediatrics, University of Cambridge, Addenbrooke’s Hospital, Level 8, Box 116, Cambridge CB2 2QQ, U.K. E-mail: dbd25{at}cam.ac.uk
Abstract
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.
Footnotes
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- Accepted January 5, 2004.
- Received September 5, 2003.
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