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Carcinogenesis Advance Access originally published online on August 27, 2007
Carcinogenesis 2007 28(10):2154-2159; doi:10.1093/carcin/bgm190
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

IGF-1 and IGFBP-3 gene variants influence on serum levels and prostate cancer risk in African-Americans

Wenndy Hernandez1,3, Cassandra Grenade2, Eunice R. Santos3, Carolina Bonilla4, Chiledum Ahaghotu5 and Rick A. Kittles1,3,*

1 Cancer Biology Program, Division of Biological Sciences, The University of Chicago, Chicago, IL 60637, USA
2 College of Medicine, Ohio State University Medical Center, Columbus, OH 43210, USA
3 Section of Genetic Medicine, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA
4 Department of Clinical Pharmacology, University of Oxford, Oxford OX2 6HA, UK
5 Division of Urology, Howard University Hospital, Washington, DC 20060, USA

* To whom correspondence should be addressed. Tel: +1 773 834 2271; Fax: +1 773 702 2567; Email: rkittles{at}medicine.bsd.uchicago.edu


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 
Insulin-like growth factor (IGF)-1 and Insulin-like growth factor binding protein-3 (IGFBP-3) are strong inhibitors of apoptosis and play a role in mediating the effects of growth hormone. Both IGF-1 and IGFBP-3 serum levels have been linked to cancer risk. Here, we explore the relationship between three common IGF polymorphisms [C/T single-nucleotide polymorphism (SNP) (rs7965399) and a dinucleotide repeat (CA)n within the 5' regulatory region of the IGF-1 gene and the –202 A/C SNP in the IGFBP-3 gene], serum levels and prostate cancer (Pca) risk in 767 African-Americans enrolled in a clinic-based case–control study. IGF-1 and IGFBP-3 levels were measured using immunochemiluminometric assay and the three polymorphisms were typed for 401 Pca cases and 366 age- and ethnicity-matched controls. Multiple linear regression and multivariable unconditional logistic regression were used to test for associations between genotypes and circulating IGF levels and Pca risk, respectively. The presence of at least one copy of the IGFBP-3 –202 C allele was strongly associated with lower IGFBP-3 serum levels (3532 versus 3106 ng/ml; P = 0.008). We also observed a 2-fold increase in Pca risk for individuals homozygous for the IGFBP-3 –202 C allele [odds ratio = 2.4; 95% confidence interval = 1.2–4.8). Furthermore, IGF-1 (CA)19 genotypes were significantly associated with lower IGFBP-3 serum levels (P = 0.003). Our results reveal that variation in the 5'-untranslated region of the IGF-1 and IGFBP-3 genes may be influencing IGF serum levels and Pca risk in African-Americans and suggest a need to explore this variation across diverse populations. Our study adds clarity and further support to the previous findings, implicating serum IGFBP-3 levels and the IGFBP-3 –202 A/C SNP in prostate carcinogenesis.

Abbreviations: BMI, body mass index; CI, confidence interval; GH, growth hormone; IGF, insulin-like growth factor; OR, odds ratio; Pca, prostate cancer; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism; IGFBP-3, Insulin-like growth factor binding protein-3


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
The American Cancer Society has estimated that in 2007 ~218 000 men will be diagnosed with prostate cancer (Pca) and >27 000 will die from the disease making Pca the second leading cause of cancer deaths among men (1). The incidence and mortality of Pca varies significantly across ethnic groups with African-American men having the highest rates in the world. In the USA, African-Americans are 1.6 and 2.4 times more likely to be diagnosed and die from Pca, respectively, than white men (1).

Insulin-like growth factors (IGFs) are essential mediators of cell growth, differentiation, apoptosis and transformation and are modulated by binding proteins, proteases and receptors (2). IGF-1 is more active post-natal and almost all mammalian cells can synthesize and export IGF-1 (3). The IGF-1 gene is located on chromosome 12, consists of 72 amino acid residues and has two promoters whose transcriptional initiation in conjunction with alternative splicing generate multiple mRNA species that allows tissue-specific expression of the transcripts (4,5). The bioavailability of IGF-1 is predominantly determined by Insulin-like growth factor binding protein-3 (IGFBP-3), a large binding protein that has a high affinity for IGF-1 and is the most abundant form of IGFBP in serum; this accounts for the fact that it binds >90% of IGF-1 (2,6,7). Aside from modulating IGF-1 bioactivity, IGFBP-3 is capable of biological actions independent of its ability to bind to IGFs. The IGFBP-3 gene is located on chromosome 7 (6).

Both IGF-1 and IGFBP-3 concentration in serum and tissue are influenced by multiple hormones, diet, ethnicity, age and sex. Growth hormone (GH) is the primary regulator of IGF-1 and, to some extent, serum levels of IGF-1 are used clinically as an indicator of GH status (3). GH also regulates the circulating levels of IGFBP-3 but this effect is believed to be mediated by IGF-1 levels (7). Aging inversely affects IGF-1 and IGFBP-3 serum levels and this may be due to a decline in GH production; however, one study found that a polymorphism in the IGF-1 gene contributed to the age decline in serum levels as well (3,8). Nutritional regulation can also impact IGF-1 and IGFBP-3 synthesis. Calories in the diet derived from fat, such as red meat, can increase IGF-1 serum levels; in contrast, those derived from carbohydrates have a negative association and consumption of saturated fat was inversely associated to IGFBP-3 serum levels (9). IGF levels have also been shown to significantly differ between ethnic groups; in the USA, African-Americans have lower IGF-1 and IGFBP-3 serum concentrations than European Americans (10,11).

In vitro studies have shown that IGFs play strong mitogenic and anti-apoptotic roles on various cancer cells and the association between IGFs and cancer is further supported by epidemiologic studies which have found that high levels of IGF-1 or in relation to low levels of IGFBP-3 increase the risk of cancer, including Pca (12). In addition, genetic studies have linked IGF-1 and IGFBP-3 variants to serum levels (13–15) and two common IGF-1 polymorphisms to Pca risk (14,16,17).

In this study, we conducted an independent case–control analysis to determine if two polymorphisms within IGF-1 and one single-nucleotide polymorphism (SNP) in the IGFBP-3 gene were associated with variation in serum IGF levels and risk for Pca in African-American men. We chose two polymorphisms in the IGF-1 gene: rs7965399 (C/T) and the cytosine–adenosine (CA)n dinucleotide repeat located 17 and 1 kb upstream of the transcription start site, respectively, because of their previous link to Pca risk and aggressiveness (14,16,17) and the functional rs2854744 (–202 A/C) SNP in the IGFBP-3 gene. We also examined IGF-1 and IGFBP-3 serum levels and risk of Pca. Given the ethnic differences in IGF serum levels and allele frequencies, statistical tests for association were performed which adjusted for individual genetic ancestry in order to control for confounding due to recent admixture in the African-American population.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Subjects
Unrelated men (N = 767) self-described as African-American were recruited between the years 2001 and 2004 from the Division of Urology at Howard University Hospital in Washington, DC. Incident sporadic Pca cases (N = 366) were identified by an urologist within the division or study coordinator and confirmed by review of medical records. Healthy control subjects (N = 401) unrelated to the cases and matched for age (±5 years) were also ascertained from the Pca-screening population of the Division of Urology at Howard University Hospital. Individuals who were ever diagnosed with benign prostatic hyperplasia and/or had an elevated prostate-specific antigen test (>2.5 ng/ml) or had an abnormal digital rectal examination were not included as controls. The demographic characteristics of participants in the screening program were similar to the patient population seen in the Division of Urology Clinics (Table I). Recruitment of sporadic Pca cases and healthy controls occurred concurrently, and they each donated a blood sample for research purposes. The participation response rates for cases and controls were 92 and 90%, respectively. All participants were between 40 and 85 years of age. Clinical characteristics including Gleason grade, prostate-specific antigen, age at diagnosis and family history were obtained for all cases from medical records. Disease aggressiveness was defined as ‘low’ (Gleason grade < 8) or ‘high’ (Gleason grade ≥ 8). The Howard University Institutional Review Board approved the study and written consent was obtained from all participants.


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  		Table I. Clinical characteristics of prostate cancer cases and controls

 
Laboratory assays
Serum IGF-1 and IGFBP-3 concentrations were measured by an immunochemiluminometric assay at Laboratory Corporation of America in Herndon, VA. All polymerase chain reactions (PCRs) were performed from DNA extracted from whole blood using unlabeled primers obtained from Integrated DNA Technologies (Coralville, IA). The total PCR volume was 20 µl and was composed of 30 ng genomic DNA, 1 U AmpliTaq polymerase (PerkinElmer, Foster City, CA), 10x PCR buffer II (PerkinElmer), 2.0 mM MgCl2, 0.6 mM deoxyribonucleotide triphosphate and 12 pmol of each primer.

The IGF-1 (CA)n thermocycler conditions included 40 cycles of touchdown beginning at 54°C and the final extension was maintained for 30 min. Primers were designed to yield a 165 bp fragment for the (CA)19 repeat. PCR products were then analyzed and fragments size labeled using the HDA-GT12 Genetic Analyzer (eGENE, Irvine, CA) using a 50–300 bp alignment marker, method OM900, baseline filter of 40, 10% positional threshold, 1.00 minimum distance, 2.0 suspended integration and 50 Points for data smoothing filter.

PCR products containing the two SNPs, IGF-1 rs7965399 (C/T) and the IGFBP-3 rs2854744 (–202 A/C), were directly digested using restriction enzymes according to the manufacturer's recommendation (New England BioLabs, Beverly, MA). Reaction conditions included 42 cycles of touchdown beginning at 58°C. Restriction enzyme digestion was performed overnight in 10 µl PCR product of each amplicon, using 1.5 U each corresponding enzyme. The resultant fragments were electrophoresed on a 2–4% agarose gel containing ethidium bromide, and bands were then visualized by ultraviolet trans-illumination. Primer sequences and restriction enzymes used in the digestion for SNP genotyping are available upon request.

A panel of 34 ancestry informative markers was also genotyped for all samples in order to estimate individual genetic ancestry. These markers show large allele frequency differences (delta, {delta}) between the ancestral populations for African-Americans (West Africans and Europeans) and were used to control for the presence of population stratification due to admixture (18–20). The description of this marker set has been provided in the previous papers (18,21). Information regarding primer sequences, polymorphic sites and other relevant information on the ancestry informative markers is available upon request. Genotyping reproducibility was >99% for replicate blinded samples.

Statistical analysis
Frequencies for both SNPs and the (CA)n polymorphism were calculated for cases and controls and genotype frequencies were tested for Hardy–Weinberg equilibrium using the {chi}2 test. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between Pca risk and aggressiveness were calculated using binary logistic regression. Linear logistic regression was used to calculate the R2 and P values for serum levels and alleles. The IGFBP-3 rs2854744 A/C SNP was modeled as three genotypes, AA (referent), AC and CC and also combined AA/AC (referent) versus CC. The same model was used for the IGF-1 rs7965399 C/T SNP. For the IGF-1 (CA)n polymorphism, the three most frequent alleles were analyzed by repeat length, presence of allele and homozygous versus others.

IGF-1 and IGFBP-3 serum levels and IGF-1:IGFBP-3 ratios were evaluated as dependent outcomes. The molar ratio was obtained as follows: IGF-1:IGFBP-1 = [IGF-1 (ng/ml) x 0.130]/[IGFBP-3 (ng/ml) x 0.036] (22). Serum IGF variables were normally distributed and thus were not transformed. We explored the relationship between each covariate and IGF levels. Covariates with significant P values were included in the final model. Statistical control for stratification due to population admixture was achieved by introducing individual ancestry for each subject as a continuous covariate in the regression analyses. Individual ancestry was estimated using the 34 typed ancestry informative markers and a Bayesian method implemented in the STRUCTURE 2.0 program (23). In our final models, we controlled for body mass index (BMI) (kg/m2) and individual ancestry (% West African ancestry) as continuous variables and for age at diagnosis for cases and time of ascertainment for controls (categorically < or ≥60). All statistical analysis was performed using the SPSS software (Version 14.0).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
Two polymorphisms in the transcription start site of IGF-1 and one SNP on the promoter of IGFBP-3 were genotyped in 767 African-American Pca cases and healthy controls. Characteristics of our study population are listed in Table I. The mean age for patients (at diagnosis) was 68.8 years and did not differ significantly from the mean age of 65.8 years for controls (P = 0.40). Our Pca cases did not differ significantly from the healthy controls for mean serum IGF levels, BMI or West African genetic ancestry (P > 0.19). Significant differences were observed between cases and controls for mean prostate-specific antigen levels (P < 0.001). Among the Pca cases, 57% had high-grade Pca.

Among the healthy controls, serum IGF-1 levels were positively correlated with IGFBP-3 and the ratio (P < 0.001), but was negatively correlated with age (P = 0.026) (Table II). The same trend was observed for IGFBP-3 levels. BMI was slightly correlated with IGFBP-3 levels (0.021) but not IGF-1 levels or the IGF-1:IGFBP-3 ratios. Surprisingly, West African genetic ancestry was not correlated with IGF serum levels in our healthy African-American controls (Table II).


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  		Table II. Bivariate correlations and corresponding P values for the relationship between serum IGF-1 and IGFBP-3 and continuous covariates among healthy African-American men from Washington, DC

 
IGF-1 and IGFBP-3 serum levels were not associated with Pca risk but they were significantly associated with aggressiveness (Table III). Significant decrease in risk for aggressive disease was observed among individuals in the second quartile for IGF-1 when compared with the lowest quartile (OR = 0.16; 95% CI = 0.04–0.62). The same was true for individuals in the second quartile for IGFBP-3 serum levels (OR = 0.16; 95% CI = 0.04–0.66). Table III shows that overall there appears to be a trend of lower risk for Pca and aggressive disease with high IGF-1 and IGFBP-3 serum levels.


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  		Table III. Adjusted ORs for Pca and disease aggressiveness by quartile of serum IGF-1 and IGFBP-3

 
Figure 1 reveals the distribution of IGF-1 allele frequencies among the African-American cases and controls. The allele frequencies differed slightly from the published frequencies of other ethnic groups (13,14,17). For instance, the number of repeats for the IGF-1 (CA)n polymorphism ranged from 13 to 45 and the most common alleles were (CA)20 (25%) followed by (CA)21 (20.7%) and (CA)19 (15.6%) among cases and controls. Cases had a lower frequency of alleles (CA)20 and (CA)21 (23.2 and 18.3%) than controls (26.4 and 22.2%) and a higher frequency of alleles (CA)19 and (CA)22 than controls. For the IGF-1 C/T SNP, the C allele had a frequency of 33% and the T allele 67% and for the IGFBP-3 –202 A/C SNP, the A allele was observed at 53% among the cases and 47% among the controls. Genotypes for all three IGF polymorphisms were in Hardy–Weinberg equilibrium independently and in controls (P > 0.05).


Figure 1
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  		Fig. 1. IGF-1 (CA)n allele frequency distribution in African-American Pca cases and healthy controls.

 
Linear regression analyses were performed to determine the relationship between IGF-1 and IGFBP-3 polymorphisms and serum levels. We observed a trend among controls with the (CA)19 repeat allele and lower mean IGF-1 and IGFBP-3 serum levels; however, only IGFBP-3 levels were significantly reduced (P = 0.001) (Table IV). The IGF-1 gene C/T SNP was not significantly associated with serum IGF levels (Table IV). The presence of the C allele for IGFBP-3 –202 A/C was significantly associated with lower IGFBP-3 serum levels (P = 0.008) when compared with AA homozygotes (3532.39 versus 3106.02). The IGFBP-3 SNP was not associated with IGF-1 serum levels. None of the three polymorphisms typed appear to influence IGF-1:IGFBP-3 ratios.


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  		Table IV. Association of IGF polymorphisms and serum levels among African-American healthy controls

 
We compared the most common repeats individually versus all others and found no significant association to Pca risk (Table V). The same result was obtained for the IGF-1 gene C/T SNP; it was not significantly associated with either Pca risk or aggressiveness. However, for the IGFBP-3 –202 A/C SNP, individuals homozygous for the C allele had an increased risk for developing Pca, see Table V (OR = 2.4, 95% CI = 1.2–4.8, P = 0.01) as well as Pca aggressiveness [OR = 2.6, 95% CI = 1.02–6.6, P = 0.04 (data not shown)].


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  		Table V. Adjusted ORs and 95% CI for associations between IGF-1 rs7965399 C/T, IGF-1 (CA)n repeats and IGFBP-3 –202 A/C genotypes and Pca risk in African-Americans

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
It is largely unknown why African-American men are disproportionately affected with Pca but it is likely due to combined genetic and environmental factors. Because many low-penetrance alleles, which confer a moderate increase in susceptibility, have been known to be highly polymorphic within and between ethnic groups, it is important to examine these alleles in diverse populations. Studies on the association of IGF-1 and IGFBP-3 serum levels, as well as their corresponding genetic variants, to Pca risk and aggressiveness have been inconsistent. The most examined variant has been the IGF-1 (CA)n repeat, with the main focus on (CA)19.

In this study, we sought to identify the relationship between IGF-1 and IGFBP-3 polymorphisms and corresponding serum levels to Pca risk and aggressiveness. We found that individuals with the CC genotype for the IGFBP-3 –202 A/C SNP are 2.4 times more likely to develop Pca and 2.6 times more likely to develop aggressive cancer. In turn, this genotype also was associated with low IGFBP-3 serum levels supporting the previous observations that a lower level of IGFBP-3 serum increases the risk for Pca. Furthermore, in an in vitro study, the promoter activity of the C allele at the –202 locus was significantly lower compared with the A allele (24).

Neither of the two IGF-1 polymorphisms [rs7965399 C/T SNP and IGF-1 (CAn)] were associated with Pca risk or aggressiveness, even though there were some noteworthy differences between the CA19 repeat allele frequency distribution among cases and controls. Our null result for the IGF-1 (CA)n polymorphism is in accordance with several previous studies (25–28). The rs7965399 C/T SNP had been previously identified to be significantly associated with Pca risk in a multiethnic cohort (16) with C allele frequencies among their African-American population quite similar to ours, 30.6 and 33% respectively; but the possibility that a second IGF-1 variant, rs7978742 found in close proximity, is responsible for the result should not be ruled out.

In another study conducted among African-Americans, IGF-1 (CA)19/(CA)19 genotypes were significantly associated with lower Pca risk but not IGFBP-3 –202 A/C, although the C allele showed a non-significant increased risk (14). Other studies also have not found an association between IGFBP-3 serum levels or IGFBP-3 variants, including –202 A/C SNP with Pca risk (26,29). Two possibilities for the lack of consensus may be due to differences in vitamin D levels and prevalence of inflammation in the study populations. Vitamin D has been shown to increase levels of IGFBP-3 (30) and therefore factors affecting levels of vitamin D, such as geographical location, dietary intake and skin color may in turn influence IGFBP-3 levels. It is also becoming increasingly known that inflammation is a strong modulator of the IGF/IGFBP system (31–33).

In our case–control association analysis, we tried to minimize and control for several potential biases which could affect our results. In our statistical analyses, we controlled for biases due to differences in ancestral proportions among our Pca cases and controls. This was warranted, given the recent admixture of African-Americans, and differences in IGF allele frequencies and Pca prevalence between African and European descent populations. Other sources of bias which would affect our case–control study include recall and potential misclassification of controls as well as benign prostatic hyperplasia history among cases. Personal in-depth interviews to assess family history among our cases were followed-up by home telephone calls in order to reduce recall bias. In order to minimize undiagnosed Pca in the controls, we conducted prostate-specific antigen assays on all controls and excluded those individuals with >2.5 mg/ml. Furthermore, we note that in our study serum IGF concentrations were determined by immunochemiluminometric assay, which differs from the more commonly used DSL enzyme-linked immunosorbent assay method. Immunochemiluminometric assay has an estimated coefficient of variation of <7% and serum determinations are comparable with other methods including DSL enzyme-linked immunosorbent assay (34,35).

We observed that neither IGF-1 nor IGFBP-3 serum levels were related to West African genetic ancestry. This is surprising, given the abundance of data revealing differences in IGF levels across ethnic groups (10,11,36). The lack of association between serum levels and West African genetic ancestry suggests that it is likely that dietary and lifestyle factors are driving the ethnic differences in serum levels observed by previous investigators. In fact, it has been shown recently that the impact of several nutritional factors such as calcium, dairy products and vegetables on IGF levels was quite different between African-American and European American males (37). Another surprising finding was the lack of association between BMI and IGF-1 serum levels. However, this is in accordance with two other studies conducted among African-American men and African Caribbean men and women (10,11) where, unlike what was found among other ethnic groups, BMI was not associated with IGF serum levels. Combined, all these findings suggest that environmental factors such as dietary intake, lifestyle and demographic factors probably play a stronger role in ethnic variation in serum IGF levels and could potentially contribute to the different results observed among studies.

Findings for the role of IGF-1 and IGFBP-3 variants in Pca vary tremendously, but their role on serum levels is becoming clear. Our study and a previous study (22) found individuals with the (CA)19/(CA)19 genotype had significantly lower IGFBP-3 levels in comparison with all other genotypes. The (CA)19 repeat allele may be an informative marker in linkage disequilibrium with an unknown functional allele and to complicate matters more, the IGF-1 gene has two promoters which initiate transcription, alternate splicing and tissue-specific expression, resulting in a variety of mRNA transcripts. Yet another factor that may influence the results is acid-labile subunit. In addition to binding to IGFBP-3, >75% of IGF-1 forms a trimeric complex with acid-labile subunit and all the three components are induced by GH and therefore deficiency or excess of GH can alter IGF-1 and IGFBP-3 serum levels (3). Our work supports the idea that variation in the IGF-1 and IGFBP-3 genes can affect serum levels. It has been assumed by some that when the level of serum IGF-1 is high, the level of serum IGFBP-3 is low and vice versa. However, the inverse relationship of IGF-1 and IGFBP-3 serum levels occurred only in <13% of our sample and has been previously noted to occur in even lower frequencies (38).

The alarming disproportionate in prevalence of Pca mortality among African-Americans merits further study. By identifying the potential influences of genetic susceptibility, we may learn more about the etiology of the disease and subsequently improve our abilities to successfully prevent, diagnose and treat human Pca. Our study further supports previous research that concluded the serum level of IGF-1 is not associated to Pca risk and that the two polymorphisms, rs7965399 C/T SNP and IGF-1 (CA)n repeat, do not affect IGF-1 serum levels nor Pca risk. Our findings also demonstrate that IGFBP-3 serum levels are not associated with Pca risk but the C allele of the –202 A/C SNP increases risk and lowers IGFBP-3 serum levels. However, given the uncertainty in the impact of these genotypes with varying environmental influences and the high amount of aggressive disease in our Pca population, the associations need to be interpreted cautiously.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
National Institutes of Health (5U54CA91431-01 and S06GM08016); Department of Defense (DAMD17-00-1-0025, DAMD17-02-1-0067 and DAMD: 17-03-1-0513).


   Acknowledgments
 
The authors would like to thank all the men who volunteered to participate in this genetic study. We would also like to thank Dr F.Akereyeni for technical assistance and useful comments.

Conflict of interest statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

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Received May 29, 2007; revised August 2, 2007; accepted August 14, 2007.


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