AIMS/HYPOTHESIS: Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism. MATERIALS AND METHODS: Variants in IGF1 were identified by direct resequencing of the exons, exon-intron boundaries and 5' and 3' regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent-child trios). We also genotyped a previously reported CA repeat in the region 5' to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) > or =0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action. RESULTS: Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF > or = 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5' to IGF1 showed no association with any phenotype. CONCLUSIONS/INTERPRETATION: Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes

Bouatia-Naji, N

Cooper, JD

Dunger, DB

Heude, B

Lowe, CE

Ong, KK

Petry, C

Ring, SM

Todd, JA

Vella, A

PubMed

Apollo (Cambridge)

SHORT COMMUNICATIONAssociation analysis of the IGF1 gene with childhood growth,IGF-1 concentrations and type 1 diabetesA. Vella & N. Bouatia-Naji & B. Heude & J. D. Cooper &C. E. Lowe & C. Petry & S. M. Ring & D. B. Dunger &J. A. Todd & K. K. OngReceived: 7 December 2007 /Accepted: 2 February 2008 /Published online: 4 March 2008# The Author(s) 2008AbstractAims/hypothesis Insulin-like growth factor-1 is a majorchildhood growth factor and promotes pancreatic islet cellsurvival and growth in vitro. We hypothesised that geneticvariation in IGF1 might be associated with childhoodgrowth, glucose metabolism and type 1 diabetes risk. Wetherefore examined the association between commongenetic variation in IGF1 and predisposition to type 1diabetes, childhood growth and metabolism.Materials and methods Variants in IGF1 were identified bydirect resequencing of the exons, exon–intron boundariesand 5′ and 3′ regions in 32 unrelated type 1 diabetes patients.A tagging subset of these variants was genotyped in acollection of type 1 diabetes families (3,121 parent–childtrios). We also genotyped a previously reported CA repeat inthe region 5′ to IGF1. A subset of seven tag single nucleotidepolymorphism (SNPs) that captured variants with minorallele frequency (MAF) ≥0.05 was genotyped in 902children from the Avon Longitudinal Study of Parents AndChildren with data on growth, IGF-1 concentrations, insulinsecretion and insulin action.Results Resequencing detected 27 SNPs in IGF1, of which 11had a MAF>0.05 and were novel. Variants with MAF≥0.10were captured by a set of four tag-SNPs. These SNPs showedno association with type 1 diabetes. In children, globalvariation in IGF1 was weakly associated with IGF-1 concen-trations, but not with other phenotypes. The CA repeat in theregion 5′ to IGF1 showed no association with any phenotype.Conclusions/interpretation Common genetic variation inIGF1 alters IGF-1 concentrations but is not associated withgrowth, glucose metabolism or type 1 diabetes.Keywords Children . Genetic variation . Growth . IGF-1 .Insulin-like growth factor-1 .Microsatellite . Singlenucleotide polymorphism . SNP. Tag-SNPs . Type 1 diabetesAbbreviationsALSPAC Avon Longitudinal Study of Parents AndChildrenMAF minor allele frequencyDiabetologia (2008) 51:811–815DOI 10.1007/s00125-008-0970-7A. Vella and N. Bouatia-Naji contributed equally to this work.Electronic supplementary material The online version of this article(doi:10.1007/s00125-008-0970-7) contains supplementary material,which is available to authorised users.A. Vella : J. D. Cooper :C. E. Lowe : J. A. ToddJuvenile Diabetes Research Foundation/Wellcome Trust Diabetesand Inflammation Laboratory, Department of Medical Genetics,Cambridge Institute for Medical Research,University of Cambridge, Cambridge, UKN. Bouatia-Naji :B. Heude :K. K. Ong (*)MRC Epidemiology Unit, Institute of Metabolic Science,Addenbrooke’s Hospital P.O. Box 285,Cambridge CB2 0QQ, UKe-mail: ken.ong@mrc-epid.cam.ac.ukB. HeudeINSERM Unit 780, IFR69,Villejuif, FranceB. HeudeFaculty of Medicine, University Paris-Sud,Orsay, FranceC. Petry :D. B. Dunger :K. K. OngDepartment of Paediatrics,University of Cambridge, Cambridge, UKS. M. RingDepartment of Community-Based Medicine,University of Bristol, Bristol, UKPresent address:A. VellaMayo Clinic, Rochester, MN, USASNP single nucleotide polymorphismWTCCC Wellcome Trust Case Control ConsortiumIntroductionType 1 diabetes is a common autoimmune disorder that arisesby an interaction between genes and the environment. To date,ten loci have been identified including the HLA class II genes,the cytotoxic T-lymphocyte associated protein 4 (CTLA4)locus, protein tyrosine phosphatase, non-receptor type 22(lymphoid) (PTPN22), IL-2 receptor, alpha (IL2RA), inter-feron induced with helicase C domain 1 (IFIH1) and fournovel loci identified by a genome-wide association study [1].The protein products of these genes play important roles inantigen presentation and the cellular immune response,highlighting the importance of the immune system in thepathogenesis of type 1 diabetes. However, not all patients withevidence of islet autoimmunity develop complete beta cellfailure [2]. Given the evidence to suggest that early weightgain and growth in childhood are associated with type 1diabetes [3], it is possible that factors influencing insulinaction (body weight and fat mass) and islet function maypredispose to or influence the presentation of type 1 diabetes.Lower IGF-1 concentrations predict the development ofglucose intolerance in adults [4]. George et al. reported thatislet overexpression of IGF1 in diabetic mice enabled isletregeneration and gradual correction of hyperglycaemia andhypoinsulinaemia [5]. A microsatellite in the region 5′ toIGF1 has been associated with adult height, cardiovascularrisk, osteoporosis and type 2 diabetes in some [6] but not all[7] studies.Since common variation in IGF1 could alter circulatingIGF-1 concentrations and therefore body habitus, insulinaction and beta cell secretion, we sought to determine theassociations, if any, between IGF1 and circulating IGF-1concentrations, size at birth, both fasting and postprandialinsulin concentrations, and type 1 diabetes.Materials and methodsPolymorphism identificationDNA samples from 32 randomly selected type 1 diabeticprobands were amplified using specifically designed forwardand reverse primers. This provided 88% probability of detectingsingle nucleotide polymorphisms (SNPs) with minor allelefrequencies (MAF) of 0.033, 96% probability for MAF 0.05and 99.8% for MAF 0.10 [8]. Resequencing included the 3 kbregion 5′ to the gene, all exons and exon–intron boundariesand 3′ untranslated region. Four 1 kb segments in the secondintron, ~10 kb intervals apart, were also resequenced.Tag-SNP selectionThe resequencing genotype data were used to select SNPsubsets that predicted the genotypes of the remainder, using acoefficient of determination, R2, which measures the abilityto predict each known SNP genotype by linear regression onthe tag-SNP genotypes [9]. We considered only SNPs with aMAF≥0.10 in the type 1 diabetes collection and ≥0.05 in theAvon Longitudinal Study of Parents And Children(ALSPAC) cohort (for details see below and Electronicsupplementary material [ESM]), using a minimum R2 of 0.8.GenotypingAll genotyping data were double-scored to minimise error. Allgenotypes were in Hardy–Weinberg equilibrium (p>0.05).Populations studiedAll DNA samples were collected after ethics approval andinformed consent had been obtained.Type 1 diabetes family collection Type 1 diabetes familieswere of white European descent, with two parents and atleast one affected child. The populations studied have beendescribed previously [8].ALSPAC Details of this birth cohort are available on theALSPAC website (www.alspac.bris.ac.uk). The children inthis study are from a 10% ‘Children in Focus’ sub-cohort(1,335 full-term singleton infants) randomly selected from thelast 6 months of recruitment for more detailed measurementsof growth. Birthweight was noted from hospital records, andlength and head circumference were measured after birth. Atage 7 years (mean age 7.5±0.1 years), body weight andheight were measured. Body composition was assessed at age9 years by whole-body dual-energy X-ray absorptiometry.Internal SD scores were calculated for all parameters ofgrowth to adjust for age and sex. IGF-1 concentrations weremeasured in cord blood samples (birth) and in venous blood(7 or 8 years of age). Fasting insulin sensitivity was assessedby the homeostatic model assessment index (www.dtu.ox.ac.uk/homa/) and insulin secretion at 30 min post oral glucoseby the insulinogenic index at age 8 years.Statistical analysisAll statistical analyses to test the association between IGF1and type 1 diabetes were performed in either Stata (www.stata.com/) or R (www.r-project.org/) statistical systems.Additional routines may be downloaded (www-gene.cimr.cam.ac.uk/clayton/software/). Missing tag-SNP genotypes812 Diabetologia (2008) 51:811–815were imputed under the null hypothesis and were analysedusing a multilocus test [9]. The microsatellite, 5′ IGF1 CArepeat, was analysed using TRANSMIT [10]. The globaleffect of the IGF1 tag-SNP set on each outcome variable wasentered into a multi-locus regression model. R2 change wastaken as the contribution to the total variation in eachoutcome. Associations of IGF1 SNPs with growth andmetabolic phenotypes were analysed using univariateANOVA (general linear models). The association of the 5′IGF1 CA repeat was analysed by comparing the wild-typeallele (192 bp) to all other alleles [6, 7].For further details on Materials and methods section, seeESM.ResultsGenetic variation in IGF1Resequencing identified 27 novel polymorphisms consist-ing of 24 SNPs, one rare non-synonymous SNP in exon 3(Ala to Thr) and two deletion/insertion polymorphisms.Eleven SNPs had a MAF>0.05. Four tag-SNPs (Table 1)were selected and genotyped in the type 1 diabetes familiesstudied. In ALSPAC, seven tag-SNPs were selected (ESMTable 1).IGF1 and type 1 diabetesThe selected tag-SNPs were genotyped in 2,439 families(3,121 parent–child trios). The multilocus test of the IGF1tag-SNPs provided no evidence of an association with type1 diabetes (χ42=4.4; p=0.356; Table 1). The microsatellite,5′ IGF1 CA repeat, was genotyped in 2,109 families andanalysed using TRANSMIT [10]. There was no evidence ofassociation (p=0.358) (ESM Table 2).Wellcome Trust Case Control Consortium dataWe used data from the Wellcome Trust Case ControlConsortium (WTCCC) genome-wide association study [1]to test association of the extended IGF1 region with type 1diabetes. The region contained 22 SNPs. When theWTCCC data were analysed using a logistic regressionmodel adjusted for variation in allele frequencies acrossGreat Britain, no evidence of association of these SNPswithin the region was found (ESM Table 3).Association with IGF-1 concentrationsIn the ALSPAC children, multilocus regression modelsshowed that the IGF1 tag-SNP set was associated with IGF-1 protein levels at birth (R2=0.063; p=0.029) and weaklyTable 1 A summary of IGF1 tag-SNPs genotyped in 2,396 familiesParameter Tag-SNPrs35140968a rs6214 rs3730220 s6219Sequence AAATAACT[-/AT]CTCAAATAGACTTAAC[A/G]TGTTTTCTCAGGTTGG[A/T]CTCAAACTAACCTCAA[A/G]CTGTCTACAllele coding,1 (minor)/2Ins/Del A/G T/A A/GMAF in parents 0.277 0.443 0.493 0.0769Minor alleletransmissionsTransmitted 815 1309 915 446Untransmittedb 790 1386 942 446Genotype 2/2Transmitted 1,150 (53.1) 947 (33.3) 798 (33.0) 2,501 (84.8)Untransmittedb 3,478 (53.6) 2,724 (31.9) 2,352 (32.4 7,489 (84.6)Genotype 2/1Transmitted 849 (39.2) 1,382 (48.5) 885 (36.6) 423 (14.3)Untransmittedb 2,541 (39.1) 4,226 (49.5) 2,685 (37.0) 1,297 (14.7)Genotype 1/1Transmitted 166 (7.7) 519 (18.2) 737 (30.5) 27 (0.91)Untransmittedb 476 (7.3) 1,594 (18.7) 2,223 (30.6) 67 (0.8)OR for minor allele(95% CI)1.03 (0.93–1.14) 0.94 (0.87–1.01) 0.97 (0.89–1.06) 1.00 (0.88–1.14)a Deletion/insertion polymorphismbUntransmitted (pseudocontrol) genotypes are estimated as previously described [8]Multilocus test p=0.425Diabetologia (2008) 51:811–815 813associated at age 7 to 8 years (R2=0.030; p=0.055; ESMTable 4). Results of IGF-1 protein level associations withindividual SNPs are shown in Table 2. However, themultilocus IGF1 tag-SNP set did not associate with anyother childhood growth or metabolic phenotype (ESMTable 4). No associations were observed between theIGF1 CA repeat and IGF-1 concentrations or any growthor metabolic phenotype (ESM Table 5).DiscussionWe used a UK birth cohort, ALSPAC, and a largefamily collection of type 1 diabetes to explore associ-ation with a subset of SNPs generated by in-depthresequencing of the IGF1 locus. A subset of SNPs thateffectively predicted the genotype of the remainder wassubsequently genotyped in these cohorts [9]. We report noevidence to support the hypothesis that genetic variation inIGF1 is associated with major susceptibility to type 1diabetes. However, genetic variation in this locus maymodestly influence circulating IGF-1 concentrations, atleast at birth and during childhood.Prior studies examining the role of genetic variation inIGF1 in predisposition to common human disease havefocused on a microsatellite in the region 5′ to IGF1. Thisvariant has been inconsistently associated with adult heightand type 2 diabetes [6, 7]. Perplexingly, the same allele hasbeen associated with high [6] and low [7] IGF-1 concen-trations. It is possible that other common genetic variants,in different degrees of linkage disequilibrium with thisvariant, alter IGF-1 concentrations and explain the discrep-ancy in the published studies.We found no association between this microsatellite andcirculating IGF-1 concentrations, growth or type 1 diabetes.To exclude the possibility that other polymorphisms in thegene predispose to disease, we undertook a systematicanalysis of IGF1 gene variation using tagging SNPs [8].Our relatively large white type 1 diabetes family collectionof European ancestry provided ~84% power to detect acausal allele for type 1 diabetes predisposition with MAF=0.1 and OR of 1.2 at the 5% significance level. The studywas therefore adequately powered to detect weak predis-position to type 1 diabetes conferred by IGF1. We did notdirectly examine whether these variants alter the age atdiagnosis of type 1 diabetes, since there was no primaryevidence of association.The possibility remains that variation in IGF1 could alterinsulin secretion or action as well as childhood growth.Therefore, to examine these associations, we adopted thesame strategy in an established birth cohort. While wedemonstrate that common genetic variation in IGF1modestly influences circulating IGF-1 concentrations atbirth and during childhood, we did not find a majorcontribution of IGF1 to birthweight, growth or responseto oral glucose. It remains possible that maternal IGF1genotypes that influence maternal metabolism might alterbirth size, but they are unlikely to significantly impact onchildhood growth.In summary, this large systematic study shows thatcommon IGF1 variants modestly influence circulating IGF-1 concentrations at birth and during childhood. However,these variants are not associated with birthweight, child-hood growth and insulin secretion or action. Moreover theydo not alter type 1 diabetes risk.Acknowledgements We gratefully acknowledge the participation ofall of the type 1 diabetic patients and family members. We also thankthe Human Biological Data Interchange and Diabetes UK for USATable 2 IGF-1 protein levels (ng/ml) at birth and at age 7 or 8 yearsby genotypes of seven IGF1 tag-SNPs in a representative birth cohortParameter n Genotype (%) pvaluers35140968 I/D (58) I/I (35) D/D (7)At birth 315 88.1 (2.8) 91.1 (3.6) 105.0 (8.9) 0.1797 or8 years547 147.8 (2.9) 147.3(3.9)157.4 (9.1) 0.581rs6214 G/G (34) G/A (50) A/A (16)At birth 305 88.6 (3.6) 87.7 (3.2) 102.43(5.30)0.0487 or8 years556 144.1 (4.0) 148.9(3.1)155.83(5.70)0.239rs3730220 A/A (38) A/T (54) T/T (9)Birth 299 94.1 (3.8) 88.6 (2.9) 89.6 (7.4) 0.5097 or8 years548 152.0 (3.8) 145.7(3.0)141.8 (8.1) 0.331rs6219 G/G (84) */A (16)Birth 300 91.0 (2.4) 85.0 (5.7) 0.3297 or8 years547 150.1 (2.5) 138.8 (5.8) 0.072rs2946831 T/T (89) */G (11)Birth 294 90.0 (2.3) 95.2 (7.2) 0.5017 or8 years541 148.0 (2.4) 153.9 (7.1) 0.432rs3730204 T/T (97) */C (3)Birth 294 111.3(13.5)90.3 (2.3) 0.1267 or8 years548 173.8(12.9)147.5 (2.3) 0.046rs12579108 C/C (97) */A (3)Birth 301 90.0 (2.2) 101.4 (12.1) 0.3587 or8 years554 147.6 (2.3) 176.8 (15.9) 0.017Values are mean (SE) for IGF-1 concentration and per cent forgenotype*Additive models, adjusted for age and sex814 Diabetologia (2008) 51:811–815and UK multiplex families, respectively, as well as C. Ionescu-Tirgoviste and C. Guja for the Romanian families, D. Undlien for theNorwegian families and D. Savage for the Northern Ireland fam-ilies. Thanks also to GET1FIN (J. Tuomilehto, L. Kinnunen, E.Tuomilehto-Wolf, V. Harjutsalo and T. Valle) for the Finnishfamilies and to the Academy of Finland, the Sigrid JuseliusFoundation and the JDRF for funding. We are extremely gratefulto all the families who took part in the ALSPAC study, themidwives for their help in recruiting them and the whole ALSPACteam, which includes interviewers, computer and laboratory techni-cians, clerical workers, research scientists, volunteers, managers,receptionists and nurses. The UK Medical Research Council, theWellcome Trust and the University of Bristol provide core supportfor ALSPAC. We thank H. Rance, T. Hassanali, J. Hutchings, G.Coleman, S. Field, T. Mistry, K. Bourget, S. Clayton, M. Hardy, J.Keylock, P. Lauder, M. Maisuria, W. Meadows, M. Sebastian andS. Wood for preparing DNA samples. This study makes use of datagenerated by the WTCCC. A full list of the investigators whocontributed to the generation of those data is available from www.wtccc.org.uk. Funding for the project was provided by the WellcomeTrust under award 076113. A. Vella is supported by the Mayo Clinicand by the National Institutes of Health DK078646-01. B. Heude wasfunded by the Danone Institute.Duality of interest The authors declare that there is no duality ofinterest associated with this manuscript.Open Access This article is distributed under the terms of theCreative Commons Attribution Noncommercial License which per-mits any noncommercial use, distribution, and reproduction in anymedium, provided the original author(s) and source are credited.References1. Todd JA, Walker NM, Cooper JD et al (2007) Robust associationsof four new chromosome regions from genome-wide analyses oftype 1 diabetes. Nat Genet 39:857–8642. Borg H, Gottsater A, Fernlund P, Sundkvist G (2002) A 12-yearprospective study of the relationship between islet antibodies andbeta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes 51:1754–17623. Johansson C, Samuelsson U, Ludvigsson J (1994) A high weightgain early in life is associated with an increased risk of type 1(insulin-dependent) diabetes mellitus. Diabetologia 37:91–944. Yakar S,WuY, Setser J, RosenCJ (2002) The role of circulating IGF-I:lessons from human and animal models. Endocrine 19:239–2485. George M, Ayuso E, Casellas A, Costa C, Devedjian JC, Bosch F(2002) Beta cell expression of IGF-I leads to recovery from type 1diabetes. J Clin Invest 109:1153–11636. Vaessen N, Heutink P, Janssen JA et al (2001) A polymorphism inthe gene for IGF-I: functional properties and risk for type 2diabetes and myocardial infarction. Diabetes 50:637–6427. Frayling TM, Hattersley AT, Smith GD, Ben-Shlomo Y (2002)Conflicting results on variation in the IGFI gene highlightmethodological considerations in the design of genetic associationstudies. Diabetologia 45:1605–16068. Vella A, Howson JM, Barratt BJ et al (2004) Lack of associationof the Ala(45)Thr polymorphism and other common variants ofthe NeuroD gene with type 1 diabetes. Diabetes 53:1158–11619. Vella A, Cooper JD, Lowe CE et al (2005) Localization of a type 1diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76:773–77910. Clayton D (1999) A generalization of the transmission/disequilibriumtest for uncertain-haplotype transmission. Am J Hum Genet 65:1170–1177Diabetologia (2008) 51:811–815 815

Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes.

A. Vella

N. Bouatia-Naji

B. Heude

J. D. Cooper

C. E. Lowe

C. Petry

S. M. Ring

D. B. Dunger

J. A. Todd

K. K. Ong

Springer - Publisher Connector

Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes

AIMS/HYPOTHESIS: Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism.MATERIALS AND METHODS: Variants in IGF1 were identified by direct resequencing of the exons, exon-intron boundaries and 5' and 3' regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent-child trios). We also genotyped a previously reported CA repeat in the region 5' to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) &gt; or =0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action.RESULTS: Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF &gt; 0.05 and were novel. Variants with MAF &gt; or = 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5' to IGF1 showed no association with any phenotype.CONCLUSIONS/INTERPRETATION: Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes.</p

Cooper, J D

Lowe, C E

Ring, S M

Dunger, D B

Todd, J A

Ong, K K

Explore Bristol Research

A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adultonset diabetes.

A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission.

A high weight gain early in life is associated with an increased risk of type 1 (insulin-dependent) diabetes mellitus.

A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction.

Beta cell expression of IGF-I leads to recovery from type 1 diabetes.

Conflicting results on variation in the IGFI gene highlight methodological considerations in the design of genetic association studies.

Lack of association of the Ala(45)Thr polymorphism and other common variants of the NeuroD gene with type 1 diabetes.

Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag singlenucleotide polymorphisms.

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.

YakarS,WuY,SetserJ,RosenCJ(2002)TheroleofcirculatingIGF-I: lessons from human and animal models.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2292425

Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes.

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