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Association between Insulin-Like Growth Factor I (IGF-I) Polymorphisms, Circulating IGF-I, and Pre- and Postnatal Growth in Two European Small for Gestational Age Populations

Department of Endocrinology, Barts and the London Queen Mary School of Medicine, University of London (L.B.J., M.O.S., A.J.L.C.), London, United Kingdom EC1A 7BE; Goteborg Pediatric Growth Research Center, Institute for the Health of Women and Children, Sahlgrenska Academy at Goteborg University (J.D., L.G., K.A.W.), 41685 Goteborg, Sweden; and Institut National de la Santé et de la Recherche Médicale, U-457, Hôpital Robert Debré (J.L., P.C.), 75019 Paris, France

Address all correspondence and requests for reprints to: Dr. Linda B. Johnston, Pediatric Endocrine Section, Department of Endocrinology Barts and the London Queen Mary School of Medicine, West Smithfield, London, United Kingdom EC1A 7BE. E-mail: l.b.johnston{at}qmul.ac.uk.

The purpose of this study was to assess the association of IGF-I and birth size by studying small for gestational age (SGA) subphenotypes and undertaking more detailed analysis of IGF-I genetic markers. SGA subjects from Haguenau, France (n = 113), and Gothenburg, Sweden (n = 174), were studied. The Swedish subjects were subphenotyped according to postnatal growth (114 short SGA and 60 SGA catch-up). IGF-I dinucleotide repeat and single nucleotide polymorphism (SNP) markers were studied, and haplotypes were generated in the Swedish short SGA group by identity of state. Association analysis was undertaken using the Monte Carlo method of association analysis of multiallelic markers for dinucleotide repeat markers, by exact ² analysis for SNPs and by ANOVA for serum IGF-I levels. IGF-I genotype was associated with the SGA phenotype, in particular with symmetrical SGA and low birth weight, and with IGF-I levels in SGA subjects. Association with postnatal growth was different in the two populations, which may reflect the power of the smaller subphenotype groups. Haplotype analysis in the Swedish short SGA subjects showed that the region of association lay between the promoter and intron 2 of the IGF-I gene. These studies validate the association of the IGF-I gene with birth size and refine the region of association in Swedish short SGA subjects.

Abbreviations: AGA, Appropriate for gestational age; CLUMP, Monte Carlo method of association analysis of multiallelic markers; DASH, dynamic allele-specific hybridization; LD, linkage disequilibrium; SDS, SD score(s); SGA, small for gestational age; SGA_W, low birth weight; SGA_L, low birth length; SGA_LW, low birth weight and low birth length; SNP, single nucleotide polymorphism.

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