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The INS VNTR Locus Does Not Associate with Smallness for Gestational Age (SGA) but Interacts with SGA to Increase Insulin Resistance in Young Adults

INSERM Unité 690 (T.-A.V.-H., S.D., P.C., C.L.-M.) and Department of Biochemistry (D.C.), Robert Debré Hôpital, 75019 Paris, France; CNRS-8090 (E.D., P.B., D.M., P.F.), Pasteur Institute, 59021 Lille, France; and Department of Genomic Medicine (P.F.), Hammersmith Hospital, Imperial College, London W12 ONN, United Kingdom

Address all correspondence and requests for reprints to: Claire Levy-Marchal, M.D., Institut National de la Santé et de la Recherche Médicale Unit 690, Robert Debré Hospital, 48, Boulevard Serurier, 75019 Paris, France. E-mail: clairelm{at}rdebre.inserm.fr.

Context: Both adverse intrauterine events and genetic background have been suggested to promote insulin resistance in subjects born small for gestational age (SGA). Among candidate genes that potentially influence both fetal growth and glucose metabolism is insulin. The potential effect of the insulin gene VNTR (INS) on birth weight has been controversial so far.

Objective: The present association study aimed at testing for the contribution of the INS VNTR locus on birth weight and on the metabolic profile of young adults born SGA (mean age, 22 yr). Two groups of subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 735), and appropriate for gestational age (AGA; birth weight between 25th and 75th percentiles; n = 886). All subjects were genotyped for rs689 A/T single nucleotide polymorphism, in complete linkage disequilibrium with the INS VNTR classes I and III, respectively.

Results: Class I INS frequencies were similar in the two groups (70% in AGA; 72% in SGA; P = 0.42). There was significant effect on mean birth weight in neither SGA (P = 0.99) nor AGA (P = 0.18). Although the INS VNTR locus did not associate with anomalies of insulin resistance indices in the AGA group, in the SGA group, INS VNTR class III allele was associated with higher insulin resistance (quantitative insulin sensitivity check index = 0.38 vs. 0.39; P = 0.05). Furthermore, there was evidence of an interaction between the SGA/AGA status and INS VNTR locus on insulin resistance indices (P = 0.01) in a multivariate analysis.

Conclusion: The INS VNTR locus does not associate in a major way with SGA in the French population. However, our data support an interaction between severe fetal growth restriction and INS VNTR locus, which were associated with insulin resistance in young adults born SGA.

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