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Serum Insulin-like Growth Factor I (IGF-I) Concentration in Men Is Not Associated with the Cytosine-Adenosine Repeat Polymorphism of the IGF-I Gene¹

Cancer Research United Kingdom Epidemiology Unit, University of Oxford, Oxford OX2 6HE, United Kingdom [N. E. A., G. K. D., T. J. K.], and Centre for Research on Women’s Health, University of Toronto, Toronto, Ontario, M5G 1N8 Canada [S. Z., S. A. N.]

	Introduction

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IGF-I³ is a polypeptide involved in the control of mitogenesis, cell-cycle regulation, and cell survival. Prospective epidemiological studies suggest that elevated levels of IGF-I, either as absolute concentrations or relative to levels of insulin-like binding protein-3 (IGFBP-3), are a risk factor for the development of several common types of cancer (1) . IGF-I levels vary substantially between individuals, and it has been estimated that up to 60% of the between-person variability has a genetic basis (2) , although the specific loci involved are unknown. A microsatellite polymorphism, comprising a variable length CA repeat sequence, has been identified in the promoter region of the IGF-I gene, 1 kb upstream from the IGF-I transcription initiation site, a region that contains specific regulatory agents (3) . The functional significance of this polymorphism is not yet known, although it may alter promotional activity and, thus, influence the transcription rate of IGF-I. The number of repeat units in the CA polymorphism range from 11 to 24 repeats; the most common allele has 19 repeats (CA19). In a previous study of 116 white men and women, the homozygous CA19/CA19 genotype was associated with a 16% lower serum IGF-I concentration than were other genotypes (3) . Another study found 78 black American women to have a lower prevalence of the CA19 allele than did 329 Caucasian women, as well as higher mean circulating IGF-I levels (4) , which parallels their increased breast cancer risk. However, among these premenopausal women, an association between the CA19 allele and IGF-I levels was reported only among users of oral contraceptives (4) . The aim of this study was to test the hypothesis that the 19-repeat allele of the IGF-I gene (CA19) is associated with a lower circulating IGF-I concentration in Caucasian men.

	Materials and Methods

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This study is based on a sample of 696 men recruited from the Oxford, United Kingdom component of EPIC. All of the men were of Caucasian origin with a mean age of 47 years (range, 20–78 years); a detailed description of subject recruitment and inclusion criteria is published elsewhere (5) . DNA was purified from 0.5 ml of buffy coat samples of peripheral blood using Nucleon BACC2 kits according to the manufacturer’s instructions (Nucleon ST, Glasgow, Scotland). Genotyping was completed using a PCR-RFLP method as described by Jernström et al. (4) . The number of repeat elements was determined and genotypes were defined according to the presence or absence of a CA19 repeat allele. Measurements of serum IGF-I concentration were performed at the Clinical Biochemistry Laboratory at the John Radcliffe Hospital, Oxford, as described previously (5) . IGF-I concentrations were square-root transformed to approximate a normal distribution; all mean values and corresponding 95% confidence intervals are presented as back-transformed values. The mean IGF-I concentration in each genotype was calculated using analysis of covariance after adjustment for age, body mass index [weight (kg)/height (m²)], dietary group, smoking status, and days between venipuncture and blood processing. All of the statistical analyses were performed using Stata version 5.0.

	Results

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Genotyping was successful for 660 (95%) of 696 study participants. The CA repeat sequences ranged from 11 to 24, although 19CA repeats were the most common, with an allele frequency of 64%. Two hundred and seventy (40.9%) subjects had two CA19 repeat alleles, 308 (46.7%) had one CA19 repeat allele, and 82 (12.4%) had no CA19 repeat alleles. The genotype frequencies were in Hardy-Weinberg equilibrium (P = 0.95) and are consistent with previous data (4) . We found no evidence to suggest that the presence of the CA19 repeat allele was associated with a lower (or higher) serum IGF-I concentration, either before or after adjustment for possible confounders (Table 1) . Similarly, there was no trend between increasing length of the repeat allele and IGF-I concentration (data not shown).

	Discussion

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	Acknowledgments

 
We thank all of the participants of the EPIC study and the EPIC study staff at ICRF, Dr. Dennis Quantrill and staff at the Clinical Biochemistry Laboratory at the John Radcliffe Hospital, Oxford.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the Imperial Cancer Research Fund and by the Europe Against Cancer Programme of the Commission of the European Communities.

² To whom requests for reprints should be addressed, at Naomi Allen, Cancer Research UK Epidemiology Unit, University of Oxford, Gibson Building, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom. Phone: 44-(0)-1865-311933; Fax: 44-(0)-1865-310545; E-mail: naomi.allen{at}cancer.org.uk

³ The abbreviations used are: IGF-I, Insulin-like growth factor-I; CA, cytosine-adenosine; EPIC, European Prospective Investigation into Cancer and Nutrition.

Received 10/ 1/01; revised 11/18/01; accepted 12/20/01.

	References

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2. Hong Y., Pedersen N. L., Brismar K., Hall K., de Faire U. Quantitative genetic analyses of insulin-like growth factor I (IGF-I), IGF-binding protein-1, and insulin levels in middle-aged and elderly twins. J. Clin. Endocrinol. Metab., 81: 1791-1797, 1996.[Abstract]
3. Rosen C. J., Kurland E. S., Vereault D., Adler R. A., Rackoff P. J., Craig W. Y., Witte S., Rogers J., Bilezikian J. P. Association between serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density. J. Clin. Endocrinol. Metab., 83: 2286-2290, 1998.[Abstract/Free Full Text]
4. Jernström H., Chu W., Vesprini D., Tao Y., Majeed N., Deal C., Pollak M., Narod S. A. Genetic factors related to racial variation in plasma levels of insulin-like growth factor-1: implications for premenopausal breast cancer risk. Mol. Genet. Metab., 72: 144-154, 2001.[Medline]
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