Null Results in Brief Serum Insulin-like Growth Factor I ( IGF-I ) Concentration in Men Is Not Associated with the Cytosine-Adenosine Repeat Polymorphism of the IGF-I Gene 1

Introduction IGF-I 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 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 (m)], dietary group, smoking status, and days between venipuncture and blood processing. All of the statistical analyses were performed using Stata version 5.0.