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Lack of Support for a Role of the Insulin Gene Variable Number of Tandem Repeats Minisatellite (INS-VNTR) Locus in Fetal Growth or Type 2 Diabetes-Related Intermediate Traits in United Kingdom Populations

Department of Diabetes and Vascular Medicine, Peninsula Medical School (S.M.S.M., A.T.H., B.K., T.T., T.M.F.), Exeter, United Kingdom EX2 5AX; Department of Endocrinology and Metabolism, Peninsula Medical School (B.S.M., L.D.V., T.J.W.), Plymouth, United Kingdom PL6 80H; University of Wales College of Medicine (D.D.), Cardiff, United Kingdom; and University of Bristol School of Social Medicine (A.M., G.D.S., Y.B.-S.), Bristol, United Kingdom BS2 8DZ

Address all correspondence and requests for reprints to: Dr. Timothy M. Frayling, Department of Diabetes and Vascular Medicine, Peninsula Medical School, Barrack Road, Exeter, United Kingdom EX2 5AX. E-mail: t.m.frayling{at}exeter.ac.uk.

The insulin gene variable number of tandem repeats minisatellite (INS-VNTR) class III allele is associated with altered fetal growth, type 2 diabetes risk (especially when paternally inherited), and insulin and IGF2 gene expression. Further studies are needed to establish the role of the INS-VNTR in fetal growth and assess whether its effects depend on the parent of origin. We analyzed the INS-VNTR-linked -23 Hph1 polymorphism in 2283 subjects, comprising 1184 children and 1099 parents. There were no differences (P < 0.05) in birth weight between offspring of the three genotypes: III/III (n = 108) vs. I/I (n = 558), effect size, -8 g (P = 0.87); and I/III (n = 464) vs. I/I, effect size, -19 g (P = 0.54). We observed no differences in head circumference [III/III (n = 95) vs. I/I (n = 470), effect size, -0.14 cm; P = 0.31] or birth length. No differences were observed when stratifying by postnatal growth realignments [nonchangers III/III (n = 37) vs. I/I (n = 170), effect size, -43 g; P = 1.00] or by parent of origin of the class III allele (presence of paternal III allele effect size, -15 g; P = 0.74). INS-VNTR was nominally associated (P < 0.05) with body mass index and insulin resistance, but not with ß-cell function, in young adults. In the largest study to date, we found a lack of support for a role for INS-VNTR in fetal growth and nominal association with type 2 diabetes-related intermediate traits.

This work was principally supported by Diabetes UK through a studentship for S.M.S.M. The funding for the Exeter Family Study of Childhood Growth was provided by the South and West National Health Service Research Directorate. The funding for the collection of the Plymouth EarlyBirds was provided by Roche Products Ltd. The original BCG study was funded by the Department of Health and Social Security. The follow-up study was funded by grants from Diabetes UK and the British Heart Association.

A.T.H. is a Wellcome Trust Career Leave Research fellow.

T.M.F. is a career scientist of the South and West National Health Service Research Directorate.

Abbreviations: ALSPAC, Avon Longitudinal Study of Pregnancy and Childhood; BCG, Barry-Caerphilly growth cohort; BMI, body mass index; CI, confidence interval; EFS, Exeter Family Study; HOMAS, homeostasis model assessment score; INS-VNTR, insulin gene variable number of tandem repeats minisatellite.

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