Duijn, C.M. (Cornelia) van

Janssen, J.A.M.J.L. (Joop)

Lamberts, S.W.J. (Steven)

Rietveld, I. (Ingrid)

Erasmus University Digital Repository

COMMENTARYA polymorphic CA repeat in the promoter region of the insulin-like growth factor-I (IGF-I) geneIngrid Rietveld1,2, Joop A.M.J.L. Janssen1, Cornelia M. Van Duijn2 &Steven W.J. Lamberts11Department of Internal Medicine; 2Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The NetherlandsIn this issue of EJEP, Kato et al. describe their ge-notype–phenotype analysis in a small study groupcomprising both Caucasian people and African–Americans. In their study group the most frequentallele of the polymorphism in the promoter region ofthe IGF-I gene contains 18 CA repeats in both ethnicgroups and no homozygote carriers of the 19 CArepeat were found. In Whites the frequency of the 19CA repeat was significantly higher compared to Af-rican Americans. No relation was found between thenumber of CA repeats and serum IGF-I levels amongall the subjects combined or in the white or blacksubgroups separately. A positive relation was foundbetween IGF-I levels and height and cigarettesmoking, and as expected age tended to be inverselyassociated with serum IGF-I.Several points need to be addressed. One issue isthe allele that is most frequently present in the studypopulation. The IGF-I gene, which is located onchromosome 12q, contains in the promoter region amicro-satellite comprising a variable length of aCA repeat sequence. Length of the repeat sequenceranges from 10 to 24, with the most frequent allelecontaining 19 CA repeats in six previous studies allinvolving Caucasian people [1–6]. In a previous studyin African–Americans only the most frequent allelecontained 18 CA repeats [7]. This suggests that dur-ing evolution there has been a shift towards longeralleles.Kato et al. observe the 18 CA repeat allele as mostfrequent in both Caucasians and African–Americansand explain their different results by the small num-ber of subjects studied (total study group 113 subjectsconsisting of 57 African–Americans and 56 Cauca-sian people), by population admixture and/or by theuse of a different genotyping method. Studies inwhich more than 450 healthy subjects are studiedregarding the IGF-I promoter polymorphism foundan allele frequency of the 19 CA repeat allele between55.5 and 88%, with a genotype frequency for ho-mozygous carriers between 37.3 and 46.8% [3–7]. Inlarge studies a more narrow range in frequency ofhomozygous carriers of the wild type allele is ob-served than in small studies. Small sized studies cantherefore, regardless of the study design, be expectedto deviate from the population characteristics.Serum IGF-I levels differ between ethnic groups, soit is not strange to expect differences in IGF-I allelefrequencies between ethnic groups. A shift towardslonger alleles during evolution is suggested from thestudy from Kato et al. as well as that from Takacset al. In this regard the observed shorter allele inAfrican–Americans is in accordance that they repre-sent an older race than Caucasians [7]. The fact thatin Whites in the study from Kato also this allele isfound to be the most frequent implies indirectly theinvolvement of older US populations. Hardy–Wein-berg equilibrium, tested by v2 statistics was not re-jected, but this could be due to chance because of thesmall study group.Automated DNA sequencing of all samples wasdone in order to determine the length of CA repeats.Methods relying on gel electrophoresis may not besensitive enough to distinguish heterozygous alleleswith differences of one repeat. However, more recentstudies using an autosequencer described the 19 CArepeat allele in Caucasian people as the most frequent[3, 4]. Also determination of the IGF-I genotypesshould be checked by at least two different investi-gators, because the software sometimes misclassifieshomozygote carriers if the size of the peak-height ofbackground noise is higher than the peak-height ofthe PCR product.Another reason for the different outcome could bethe selection of the controls. The controls in the studyby Kato et al. were selected from an on-going hos-pital-based case–control study for prostate and breastcancer. All controls participated in the screeningprogram for prostate cancer or visited the BreastClinic but were not found to have malignant lesions.People participating in the screening programme orvisiting the Breast Clinic may have complaints whichcould be related to prostate or breast cancer. Becausethe controls do not represent a population-basedstudy group, differences in allele frequencies couldhave occurred.Another outcome from this selection is a clear de-viation of the observed mean IGF-I levels fromnormal values. The highest mean is found in theyoungest age group (six subjects in the age rangefrom 22 to 39 years of age), and is 146.6 ng/ml(=146.6 ug/L) where the normal reference range inthis age group is 114–492 ug/L [8]. The other IGF-Ilevels are also lower than expected for their age. Lowserum IGF-I levels are thought to be a consequenceof growth hormone deficiency, malnutrition, liverEuropean Journal of Epidemiology 18: 191–193, 2003. 2003 Kluwer Academic Publishers. Printed in the Netherlands.dysfunction or ageing, but also certain diseases reflectlow serum IGF-I levels [9, 10].Several studies examined the relationship betweenserum IGF-I levels and osteoporosis and cardiovas-cular diseases [1, 11, 12]. Serum IGF-I levels seem tocorrelate well with bone mineral density and couldtherefore be related to osteoporosis [1, 13]. In car-diovascular diseases, low serum IGF-I after acutemyocardial infarction has been associated with badsurvival [11]. The question remains whether the sub-jects studied by Kato et al. really represent a healthypopulation. Another problem is that different typesof specimen differ in their mean IGF-I levels. Com-mercially available kits from Medgenix and DSLstate that measurements in plasma result in lowerIGF-I levels compared to those in serum. Also asignificantly higher mean IGF-I level was observed inserum compared to EDTA plasma and heparinplasma (157.5 ± 45.6 vs. 137.8 ± 42.5 and141.3 ± 39.3; p < 0.001) [14]. The reason for therelatively low IGF-I levels in the present selectedstudy group could therefore be diverse. However,we do not have enough information to find out itscause.Kato et al. found no consistent trend in plasmaIGF-I levels by age and no relation was observedbetween IGF-I alleles and IGF-I levels. Serum totalIGF-I levels have been measured in healthy infants,children, adolescents and adults [15–18]. Levels in-crease fast during the first year of life, followed by alinear increase from early childhood into adolescence[15, 16]. During puberty a steep increase is seen toapproximately 500 ug/L and after reaching it’s maxi-mum level, IGF-I levels decline with age towardprepubertal levels in adults (approximately 300 ug/L), followed by a further slow decrease until 70 yearsof age [15–17]. Lack of overall association betweenage and IGF-I levels in the present study could alsobe due to the small sample size and a wide age-rangeresulting in low numbers of subjects present in the agecategories.Several previous studies have been directed at thepotential functionality of this polymorphism. Resultsso far have been conflicting. Vaessen et al. observed ahigher serum total IGF-I level in homozygote carriersof the 19 CA repeat allele compared to non-carriersof this most frequent allele [4]. Frayling et al. de-scribed the opposite effect: low serum IGF-I levelswere observed in homozygote carriers of the wild typeallele compared to non-carriers of the 19 CA repeatallele [3]. Other studies did not find a relation betweenthis polymorphism and IGF-I levels [5].In conclusion, ethnicity, size of the study groupand the genotyping method used by Kato et al. mighthave blurred the precise association between thepolymorphism studied and its functional conse-quences.Reference1. Rosen CJ, Kurland ES, Vereault D, et al. Associationbetween serum insulin growth factor-I (IGF-I) and asimple sequence repeat in IGF-I gene: Implications forgenetic studies of bone mineral density. J Clin Endo-crinol Metab 1998; 83: 2286–2290.2. Arends N, Johnston L, Hokken-Koelega A, et al.Polymorphism in the IGF-I gene: Clinical relevance forshort children born small for gestational age (SGA). JClin Endocrinol Metab 2002; 87: 2720–2724.3. Frayling TM, Hattersley AT, McCarthy A, et al. Aputative functional polymorphism in the IGF-I gene:Association studies with type 2 diabetes, adult height,glucose tolerance, and fetal growth in U.K. popula-tions. Diabetes 2002; 51: 2313–2316.4. Vaessen N, Heutink P, Janssen JA, et al. A polymor-phism in the gene for IGF-I: Functional properties andrisk for type 2 diabetes and myocardial infarction.Diabetes 2001; 50: 637–642.5. Allen NE, Davey GK, Key TJ, Zhang S, Narod SA.Serum insulin-like growth factor I (IGF-I) concentra-tion in men is not associated with the cytosine-adeno-sine repeat polymorphism of the IGF-I gene. CancerEpidemiol Biomarkers Prev 2002; 11: 319–320.6. Missmer SA, Haiman CA, Hunter DJ, et al. A se-quence repeat in the insulin-like growth factor-1 geneand risk of breast cancer. Int J Cancer 2002; 100: 332–336.7. Takacs I, Koller DL, Peacock M, et al. Sibling pairlinkage and association studies between bone mineraldensity and the insulin-like growth factor I gene locus.J Clin Endocrinol Metab 1999; 84: 4467–4471.8. Greenspan FS, Gardner DG. Basic and Clinical Endo-crinology. San Fransisco: The McGraw Hill Compa-nies, 2001.9. Froesch ER, Hussain MA, Schmid C, Zapf J. Insulin-like growth factor I: Physiology, metabolic effects andclinical uses. Diabetes Metab Rev 1996; 12: 195–215.10. Rosen CJ, Pollak M. Circulating IGF-I: New per-spectives for a new century. 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Serum levels ofinsulin-like growth factor (IGF)-binding protein-3(IGFBP-3) in healthy infants, children, and adoles-cents: The relation to IGF-I, IGF-II, IGFBP-1, IG-192FBP-2, age, sex, body mass index, and pubertal mat-uration. J Clin Endocrinol Metab 1995; 80: 2534–2542.16. Juul A, Bang P, Hertel NT, et al. Serum insulin-likegrowth factor-I in 1030 healthy children, adolescents,and adults: Relation to age, sex, stage of puberty, tes-ticular size, and body mass index. J Clin EndocrinolMetab 1994; 78: 744–752.17. Ho KK, Hoffman DM. Aging and growth hormone.Horm Res 1993; 40: 80–86.18. Janssen JA, Stolk RP, Pols HA, Grobbee DE, de JongFH, Lamberts SW. Serum free IGF-I, total IGF-I,IGFBP-1 and IGFBP-3 levels in an elderly population:Relation to age and sex steroid levels. Clin Endocrinol(Oxf) 1998; 48: 471–478.Address for correspondence: Dr J.A.M.J.L. Janssen, De-partment of Internal Medicine, Room D-436, ErasmusMC, Dr Molewaterplein 40, 3015 GD, Rotterdam, TheNetherlandsPhone: þ31-10-463-9222; Fax: þ31-10-463-3268E-mail: janssen@inw3.azr.nl193

A polymorphic CA repeat in the promoter region of the insulin-like growth factor-I (IGF-I) gene

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A polymorphic CA repeat in the promoter region of the insulin-like growth factor-I (IGF-I) gene

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