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1.  Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women 
PLoS ONE  2014;9(10):e108934.
Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations.
From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels.
Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L).
IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more.
PMCID: PMC4186782  PMID: 25285521
2.  Genomewide meta‐analysis identifies loci associated with IGF‐I and IGFBP‐3 levels with impact on age‐related traits 
Teumer, Alexander | Qi, Qibin | Nethander, Maria | Aschard, Hugues | Bandinelli, Stefania | Beekman, Marian | Berndt, Sonja I. | Bidlingmaier, Martin | Broer, Linda | Cappola, Anne | Ceda, Gian Paolo | Chanock, Stephen | Chen, Ming‐Huei | Chen, Tai C. | Chen, Yii‐Der Ida | Chung, Jonathan | Del Greco Miglianico, Fabiola | Eriksson, Joel | Ferrucci, Luigi | Friedrich, Nele | Gnewuch, Carsten | Goodarzi, Mark O. | Grarup, Niels | Guo, Tingwei | Hammer, Elke | Hayes, Richard B. | Hicks, Andrew A. | Hofman, Albert | Houwing‐Duistermaat, Jeanine J. | Hu, Frank | Hunter, David J. | Husemoen, Lise L. | Isaacs, Aaron | Jacobs, Kevin B. | Janssen, Joop A. M. J. L. | Jansson, John‐Olov | Jehmlich, Nico | Johnson, Simon | Juul, Anders | Karlsson, Magnus | Kilpelainen, Tuomas O. | Kovacs, Peter | Kraft, Peter | Li, Chao | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J. F. | Lorentzon, Mattias | Lu, Yingchang | Maggio, Marcello | Magi, Reedik | Meigs, James | Mellström, Dan | Nauck, Matthias | Newman, Anne B. | Pollak, Michael N. | Pramstaller, Peter P. | Prokopenko, Inga | Psaty, Bruce M. | Reincke, Martin | Rimm, Eric B. | Rotter, Jerome I. | Saint Pierre, Aude | Schurmann, Claudia | Seshadri, Sudha | Sjögren, Klara | Slagboom, P. Eline | Strickler, Howard D. | Stumvoll, Michael | Suh, Yousin | Sun, Qi | Zhang, Cuilin | Svensson, Johan | Tanaka, Toshiko | Tare, Archana | Tönjes, Anke | Uh, Hae‐Won | van Duijn, Cornelia M. | van Heemst, Diana | Vandenput, Liesbeth | Vasan, Ramachandran S. | Völker, Uwe | Willems, Sara M. | Ohlsson, Claes | Wallaschofski, Henri | Kaplan, Robert C.
Aging Cell  2016;15(5):811-824.
The growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci.
PMCID: PMC5013013  PMID: 27329260
aging; genomewide association study; growth hormone axis; IGF‐I; IGFBP‐3; longevity
3.  Predictors of Circulating Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Protein-3 in Critical Illness 
Critical care medicine  2015;43(12):2651-2659.
To characterize predictors of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 in acute critical illness with the hypothesis that acute factors associated with critical illness will more strongly predict circulating IGF-1 and IGFBP-3 than chronic clinical or genetic factors.
Observational study nested within a large prospective study using multivariable linear regression to model circulating IGF-1 and IGFBP-3 with acute and chronic clinical variables, and genotype from five polymorphisms in IGF pathway genes.
Setting and Patients
Five-hundred forty-three Caucasian patients with risk factors for acute respiratory distress syndrome (ARDS) and available plasma from early in critical illness, recruited from intensive care units (ICUs) of two large academic medical centers.
Measurements and Main Results
Total IGF-1 and IGFBP-3 were measured in plasma using IMMULITE assays. We examined age, gender, body mass index (BMI), cirrhosis, and diabetes, as well as APACHE III score, acute hepatic dysfunction, pneumonia and aspiration, sepsis/septic shock, ARDS, and receipt of corticosteroids. BMI, cirrhosis, and ARDS were strongly associated with IGF-1 and IGFBP-3 levels; APACHE III was strongly associated with IGF-1 levels; and age was strongly associated with IGFBP-3‥ Five polymorphisms (IGF1: rs1520220, rs35767, rs2946834; IGFBP1: rs4619; IGFBP3: rs2854746) were analyzed for associations with plasma levels. When genotypes were added to models, rs2854746 was significantly associated with plasma IGFBP-3. Genotype explained an additional 2% of variability with an overall adjusted R-square of 0.18.
Despite the acute derangements of critical illness, both acute and chronic health factors significantly influence circulating levels of IGF-1 and IGFBP-3 early in critical illness. Rs2854746 is also significantly associated with IGFBP-3 levels in this ICU cohort. Overall, phenotypic and genotypic factors explained only a modest amount of variability in IGF-1 and IGFBP-3. Further research is needed to understand how to apply these findings to patient care.
PMCID: PMC4651824  PMID: 26427594
Acute respiratory distress syndrome; single nucleotide polymorphisms; insulin-like growth factor-1; insulin-like growth factor binding protein-3; molecular epidemiology; critical care
4.  Circulating insulin-like growth factor (IGF) peptides and prostate cancer risk: a systematic review and meta-analysis 
Insulin-like growth factors (IGF-I, IGF-II) and their binding proteins (IGFBP-1-6) play a key role in cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis. Several epidemiological studies show associations of IGFs with prostate cancer. We searched the published literature for all studies relating levels of IGFs or IGFBPs with prostate cancer. We performed random effects meta-analysis to calculate summary odds ratios. The number of studies (prostate cancer cases) included in each meta-analysis were 42 (7,481) IGF-I; 10 (923) IGF-II; 3 (485) IGFBP-1; 5 (577) IGFBP-2; 29 (6,541) IGFBP-3; and 11 (3,545) IGF-1:IGFBP-3 ratio. The pooled odds ratios (95% confidence intervals) per standard deviation increase in peptide, were: IGF-I, OR = 1.21 (1.07, 1.36); IGF-II, OR = 1.17 (0.93, 1.47); IGFBP-1, OR = 1.21 (0.62, 2.33); IGFBP-2, OR = 1.18 (0.90, 1.54); IGFBP-3, OR = 0.88 (0.79, 0.98); IGFI:IGFBP-3 ratio, OR = 1.10 (0.97, 1.24). For all exposures, there was substantial heterogeneity (all I2 > 75%), partly explained by study design: the magnitude of associations was smaller in prospective versus retrospective studies, and for IGFBP-3 the inverse association with prostate cancer risk was seen in retrospective but not prospective studies. There was weak evidence that associations of IGF-I and IGFBP-3 with prostate cancer were stronger for advanced disease. Our meta-analysis confirms that raised circulating lGF-I is positively associated with prostate cancer risk. Associations between IGFBP-3 and prostate cancer were inconsistent, and there was little evidence for a role of IGF-II, IGFBP-1 or IGFBP-2 in prostate cancer risk.
PMCID: PMC2743036  PMID: 19142965
prostate cancer; meta-analysis; insulin-like growth factor; insulin-like growth factor binding protein
5.  IGF-I and IGFBP-3 polymorphisms in relation to circulating levels among African American and Caucasian women 
Circulating insulin-like growth factor-one (IGF-I) and IGF binding protein-3 (IGFBP-3) levels have been associated with common diseases. Although family-based studies suggest that genetic variation contributes to circulating IGF-I and IGFBP-3 levels, analyses of associations with multiple IGF-I and IGFBP-3 single nucleotide polymorphisms (SNPs) have been limited, especially among African Americans. We evaluated 30 IGF-I and 15 IGFBP-3 SNPs and estimated diplotypes in association with plasma IGF-I and IGFBP-3 among 984 premenopausal African American and Caucasian women. In both races, IGFBP-3 rs2854746 (Ala32Gly) was positively associated with plasma IGFBP-3 (CC versus GG mean difference among Caucasians = 631 ng/ml, 95% confidence interval: 398, 864; African Americans = 897 ng/ml, 95% confidence interval: 656, 1138), and IGFBP-3 diplotypes with the rs2854746 GG genotype had lower mean IGFBP-3 levels than referent diplotypes with the CG genotype, while IGFBP-3 diplotypes with the CC genotype had higher mean IGFBP-3 levels. IGFBP-3 rs2854744 (−202 A/C) was in strong linkage disequilibrium with rs2854746 in Caucasians only, but was associated with plasma IGFBP-3 in both races. Eight additional IGFBP-3 SNPs were associated with 5% or greater differences in mean IGFBP-3 levels, with generally consistent associations between races. Twelve IGF-I SNPs were associated with 10% or greater differences in mean IGF-I levels, but associations were generally discordant between races. Diplotype associations with plasma IGF-I did not parallel IGF-I SNP associations. Our study supports that common IGFBP-3 SNPs, especially rs2854746, influence plasma IGFBP-3 levels among African Americans and Caucasians, but provides less evidence that IGF-I SNPs affect plasma IGF-I levels.
PMCID: PMC2896274  PMID: 19240240
insulin-like growth factor I; insulin-like growth factor binding protein 3; genetic polymorphisms; women; African Americans
6.  Eighteen Insulin-like Growth Factor (IGF) pathway genes, circulating levels of IGF-1 and its binding protein (IGFBP-3), and risk of prostate and breast cancer 
Circulating levels of insulin-like growth factor I (IGF-1) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-1 and IGFBP-3 in studies of adult twins.
We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-1 and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNPs) were genotyped in over 5500 Caucasian men and 5500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium (BPC3).
After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-1 (p<2.1×10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2=0.62% of the variation in circulating IGF-1 and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-1 or IGFBP-3 and risk of prostate or breast cancers.
Common genetic variation in the IGF1 and SSTR5 genes appears to influence circulating IGF-1 levels, and variation in IGFBP3 and IGFALS appears to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-1 and IGFBP-3 in Caucasian men and women.
Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.
PMCID: PMC2989404  PMID: 20810604
insulin-like growth factors; genetic association; breast cancer; prostate cancer
7.  Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels 
International Journal of Cancer  2016;139(7):1520-1533.
Circulating insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome‐wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N ∼ 900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF‐I, IGF‐II, IGFBP‐2 and IGFBP‐3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs. high (≥ 7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF‐II and IGFBP‐3, less so for IGF‐I. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF‐II/IGFBP‐3 level‐raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF‐II (∼265 ng/mL) on risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.
What's New?
Circulating insulin‐like growth factors (IGF) and their binding proteins have been associated with prostate cancer risk in observational epidemiological studies but it is not clear whether there is a causal relationship with disease. To address this question, the authors used Mendelian randomization, a method that uses genetic variants as proxies for measured exposures. Their results implicate the IGF pathway in general in prostate cancer development but specific biomarkers remain to be determined.
PMCID: PMC4957617  PMID: 27225428
insulin‐like growth factors; insulin‐like growth factor‐binding proteins; prostate cancer; Mendelian randomization; single nucleotide polymorphisms; IGFBP3; ProtecT; PRACTICAL; ALSPAC; UKHLS
8.  Genetic Variation and Circulating Levels of IGF-I and IGFBP-3 in Relation to Risk of Proliferative Benign Breast Disease 
Insulin-like growth factor-I (IGF-I) and its major binding protein IGFBP-3 have been implicated in breast carcinogenesis. We examined the associations between genetic variants and circulating levels of IGF-I and IGFBP-3 with proliferative benign breast disease (BBD), a marker of increased breast cancer risk, in the Nurses’ Health Study II (NHSII). Participants were 359 pathology-confirmed proliferative BBD cases and 359 matched controls. Circulating IGF-I and IGFBP-3 levels were measured in blood samples collected between 1996 and 1999. Thirty single nucleotide polymorphisms (SNPs) in IGF-I, IGFBP-1, and IGFBP-3 genes were selected using a haplotype tagging approach and genotyped in cases and controls. Circulating IGF-I levels were not associated with proliferative BBD risk. Higher circulating IGFBP-3 levels were significantly associated with increased risk of proliferative BBD (highest vs. lowest quartile odds ratio (OR) (95% confidence interval (CI)), 1.70 (1.06–2.72); p-trend = 0.03). The minor alleles of two IGFBP-3 SNPs were associated with lower proliferative BBD risk (homozygous variant vs. homozygous wild-type OR (95% CI): rs3110697: 0.6 (0.4–0.9), p-trend = 0.02; rs2132570: 0.2 (0.1–0.6), p-trend = 0.02). Three other IGFBP-3 SNPs (rs2854744, rs2960436, and rs2854746) were significantly associated with circulating IGFBP-3 levels (p < 0.01). Although these SNPs were not significantly associated with proliferative BBD risk, there was suggestive evidence that the alleles associated with higher circulating IGFBP-3 levels were also associated with higher risk of proliferative BBD. These results suggest that genetic variants and circulating levels of IGFBP-3 may play a role in the early stage of breast carcinogenesis.
PMCID: PMC2783930  PMID: 19551864
IGF-I; IGFBP-3; Circulating levels; Genetic Variation; Proliferative BBD
9.  Insulin-like Growth Factors, Their Binding Proteins, and Prostate Cancer Risk: Analysis of Individual Patient Data from 12 Prospective Studies 
Annals of internal medicine  2008;149(7):461-W88.
Some, but not all, published results have shown an association between circulating blood levels of some insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) and the subsequent risk for prostate cancer.
To assess the association between levels of IGFs and IGFBPs and the subsequent risk for prostate cancer.
Data Sources
Studies identified in PubMed, Web of Science, and CancerLit.
Study Selection
The principal investigators of all studies that published data on circulating concentrations of sex steroids, IGFs, or IGFBPs and prostate cancer risk using prospectively collected blood samples were invited to collaborate.
Data Extraction
Investigators provided individual participant data on circulating concentrations of IGF-I, IGF-II, IGFBP-II, and IGFBP-III and participant characteristics to a central data set in Oxford, United Kingdom.
Data Synthesis
The study included data on 3700 men with prostate cancer and 5200 control participants. On average, case patients were 61.5 years of age at blood collection and received a diagnosis of prostate cancer 5 years after blood collection. The greater the serum IGF-I concentration, the greater the subsequent risk for prostate cancer (odds ratio [OR] in the highest vs. lowest quintile, 1.38 [95% CI, 1.19 to 1.60]; P < 0.001 for trend). Neither IGF-II nor IGFBP-II concentrations were associated with prostate cancer risk, but statistical power was limited. Insulin-like growth factor I and IGFBP-III were correlated (r = 0.58), and although IGFBP-III concentration seemed to be associated with prostate cancer risk, this was secondary to its association with IGF-I levels. Insulin-like growth factor I concentrations seemed to be more positively associated with low-grade than high-grade disease; otherwise, the association between IGFs and IGFBPs and prostate cancer risk had no statistically significant heterogeneity related to stage or grade of disease, time between blood collection and diagnosis, age and year of diagnosis, prostate-specific antigen level at recruitment, body mass index, smoking, or alcohol intake.
Insulin-like growth factor concentrations were measured in only 1 sample for each participant, and the laboratory methods to measure IGFs differed in each study. Not all patients had disease stage or grade information, and the diagnosis of prostate cancer may differ among the studies.
High circulating IGF-I concentrations are associated with a moderately increased risk for prostate cancer.
PMCID: PMC2584869  PMID: 18838726
10.  Serum Levels of Insulin-Like Growth Factor (IGF); IGF-Binding Proteins-3, -4, and -5; and Their Relationships to Bone Mineral Density and the Risk of Vertebral Fractures in Postmenopausal Women 
Calcified tissue international  2006;78(1):18-24.
We previously found that serum levels of insulin-like growth factor I (IGF-I) and IGF-binding protein (IGFBP)-3, but not IFGBP-2, were associated with bone mineral density (BMD) and the risk of vertebral fractures. The aim of the present study was to investigate the roles of IGFBP-4 and -5 in age-dependent bone loss and vertebral fracture risk in postmenopausal Japanese women and to compare them with those of IGF-I and IGFBP-3. One hundred and ninety-three Japanese women aged 46–88 years (mean 62.5) were enrolled in the cross-sectional study. BMD was measured at the lumbar spine, femoral neck, ultradistal radius (UDR), and total body by dual-energy X-ray absorptiometry. Serum levels of IGFBP-4 and -5 as well as IGF-I and IGFBP-3 were measured by radioimmunoassay. Serum levels of IGF-I, IGFBP-3, and IGFBP-5 declined with age, while serum IGFBP-4 increased with age. Multiple regression analysis was performed between BMD at each skeletal site and serum levels of IGF-I and IGFBPs adjusted for age, body weight, height, and serum creatinine. BMD at the UDR was significantly and positively correlated with all serum levels of IGF-I and IGFBPs measured (P < 0.01), while BMD at the femoral neck was correlated with none of them. Serum IGF-I level was significantly and positively correlated with BMD at all sites except the femoral neck (P < 0.01), while serum IGFBP-3 and -4 levels were significantly and positively correlated with only radial BMD (P < 0.01). Serum IGFBP-5 level was positively correlated with UDR BMD (P < 0.001) and negatively correlated with total BMD (P < 0.05). Serum IGF-I, IGFBP-3, and IFGBP-5 levels were significantly lower in women with vertebral fractures than in those without fractures (mean ± SD: 97.1 ± 32.1 vs. 143.9 ± 40.9 ng/dl, P < 0.0001; 2.18 ± 1.02 vs. 3.23 ± 1.07 µg/ml, P < 0.0001; 223.6 ± 63.3 vs. 246.5 ± 71.5 ng/ml, P = 0.0330, respectively). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and serum levels of IGF-I and IGFBPs adjusted for age, body weight, height, serum creatinine, and serum alubumin as independent variables, IGF-I and IGFBP-3 were selected as indices affecting the presence of vertebral fractures [odds ratio (OR) = 0.29, 95% confidential interval (CI) 0.15–0.57 per SD increase, P = 0.0003 and OR = 0.31, 95% CI 0.16–0.61 per SD increase, P = 0.0007, respectively]. To compare the significance values, IGF-I, IGFBP-3, and age were simultaneously added as independent variables in the analysis. IGFBP-3 was more strongly associated with the presence of vertebral fractures than IGF-I and age (P = 0.0006, P = 0.0148, and P = 0.0013, respectively). Thus, after comprehensive measurements of serum levels of IGF-I and IGFBPs, it seems that serum IGF-I level is most efficiently associated with bone mass and that serum IGFBP-3 level is most strongly associated with the presence of vertebral fractures in postmenopausal women among the IGF system components examined.
PMCID: PMC2904611  PMID: 16397738
Insulin-like growth factor-binding protein; Insulin-like growth factor; Bone mineral density; Vertebral fracture; Postmenopausal women
11.  Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk 
Carcinogenesis  2009;30(12):2042-2046.
Insulin-like growth factor (IGF) 1 and its binding proteins foster cellular proliferation and inhibit apoptosis. In vitro studies show that IGF1 increases ovarian cell growth and invasive potential, suggesting a role for the IGF1 pathway in ovarian cancer etiology. We evaluated genetic variation in the IGF1, IGFBP1 and IGFBP3 genes in relation to ovarian cancer risk by genotyping 29 haplotype-tagging single nucleotide polymorphisms in 1173 cases and 1201 controls from the New England Case–Control (NECC) study and 296 cases and 854 controls from the Nurses’ Health Study (NHS). The association of haplotypes and single nucleotide polymorphisms (SNPs) with ovarian cancer was estimated using unconditional (NECC) and conditional (NHS) logistic regression. Additionally, we evaluated the association of SNPs with IGF1, IGF-binding protein (IGFBP) 3 and IGFBP2 plasma levels (n = 380 NHS controls). Our data suggest a decreased risk for women carrying haplotype 2C of the IGF1 gene [odds ratios (ORs) = 0.82, 95% confidence intervals (CIs) = 0.69–0.98] and an increased risk for women carrying haplotype 1D (OR = 1.41, 95% CI = 1.03–1.94) or 2D (OR = 1.20, 95% CI = 1.01–1.41) in the binding proteins. When evaluated individually, three SNPs in the IGFBPs (rs10228265, rs4988515 and rs2270628) were associated with increased ovarian cancer risk, and several IGF1 (rs11111285, rs1996656 and rs1019731) and IGFBP3 (rs2270628, rs2854746 and rs2854744) SNPs were significantly associated with IGF1, IGFBP3 and IGFBP2 plasma levels. Some haplotypes and SNPs in the IGF pathway genes may be associated with ovarian cancer risk; however, these results need to be confirmed. Of particular interest was the IGFBP3 SNP rs2270628, which was associated with both increased IGF1 plasma levels and higher ovarian cancer risk.
PMCID: PMC2792318  PMID: 19858071
12.  A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians† 
Human Molecular Genetics  2010;19(15):3089-3101.
The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) ≥ 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (Padj = 8.8 × 10−43) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90–1.14) and 1.20 (99% CI: 1.06–1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 × 10−3. IGF-I levels were significantly associated with PCa risk (Ptrend = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.
PMCID: PMC2901143  PMID: 20484221
13.  A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3 
Human Molecular Genetics  2011;20(6):1241-1251.
Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10−8 (P = 3.3 × 10−101). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10−26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10−21) and higher IGF-I (P = 4.9 × 10−9) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10−11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10−10, SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10−7), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
PMCID: PMC3043664  PMID: 21216879
14.  High insulin-like growth factor binding protein-1 (IGFBP-1) level predicts incident congestive heart failure in the elderly 
American Heart Journal  2008;155(6):1006-1012.
Low insulin-like growth factor–1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulin-like growth factor binding protein-1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in CHF patients and has been associated prospectively with increased mortality among older adults and myocardial infarction survivors. We investigated the association between fasting plasma levels of IGF-I, IGFBP-1, IGFBP-3, and insulin and risk of incident CHF in the prospective Cardiovascular Health Study (CHS).
From among 5,888 65+ year-old adults in the Cardiovascular Health Study (CHS), we studied 566 incident CHF cases and 1,072 comparison subjects, after exclusion of underweight individuals (BMI < 18.5 kg/m2) and insulin users. Hazard ratios (HR) with 95% confidence intervals (CIs) for CHF were estimated after adjustment for age, race, gender, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and BMI.
High baseline IGFBP-1 level was a significant predictor of CHF, independent of established CHF risk factors and inflammation markers. The HR per SD of IGFBP-1 was 1.22 (95% CI=1.07–1.39, p < 0.01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95% CI=0.96–1.74, p=0.09) for the second IGFBP-1 tertile and 1.47 (95% CI=1.06–2.04; p=0.02) for the highest IGFBP-1 tertile (tertile cutpoints 19.5 and 35.8 ng/ml). Total IGF-I, IGFBP-3, or insulin levels had no association with CHF after adjustment for CHF risk factors.
High circulating IGFBP-1 may be a CHF risk factor among older adults.
PMCID: PMC3286655  PMID: 18513511
15.  Insulin-Like Growth Factor I Receptor (IGF-IR) Ligands and BMI in Squamous Intra-Epithelial Lesion (SIL) of Cervix 
Cancer cervix is the most common cancer in women in developing countries like India. Several studies have linked insulin-like growth factors-I & II (IGF-I and IGF-II) and IGF binding proteins-3 (IGFBP-3) with pathogenesis of Squamous Intraepithelial Lesion of cervix (SIL). To the best of our knowledge, no study has shown any correlation between circulating C-Peptide levels and SIL.
The present study has attempted to evaluate the correlation between SIL and IGF-IR ligands (IGF-I, IGF-II, C-Peptide), IGF binding protein (IGFBP-3) and Body Mass Index (BMI).
Materials and Methods
The present case-control study consisted of 31 histologically proven SIL cases and 31 age matched controls without evidence of SIL. A 10 ml blood sample was collected in heparinized vial. Plasma was separated immediately using centrifugation and was stored at -800 C till further analysis. Plasma levels of IGF-I, IGF-II, C-peptide and IGFBP3 were measured using commercially available Enzyme Linked Immunosorbent Assay (ELISA) kit. Height and weight was noted for calculation of BMI. Bio-effective molar ratio (BEMR) was calculated as 3.72 x {(0.25 x IGF-I) + (0.032 x IGF-II) + (0.0025 x C-peptide)} / {(1435 + IGFBP-3) – (2.79 x IGF-I) – (2.87 x IGF-II)}. Statistical analysis was performed using SPSS and Microsoft Excel software employing student t-test, Mann-Whitney and Chi-square test for trend while binary logistic regression was used to estimate the odds ratios (OR) and corresponding 95% Confidence Intervals (CI).
IGF-I, IGF-II levels and BEMR were significantly increased in SIL compared to controls (p= 0.001, p <0.001, and p <0.001, respectively). C-Peptide levels were higher in controls than SIL (p = 0.04). IGFBP-3 & BMI in SIL were not significantly related when compared with controls. Risk of SIL in 4th quartile for BEMR, IGF-I, and IGF-II was 12.18(95% CI= 3.13-47.39), 3.94(95% CI = 1.24-12.56), and 4.57(95% CI = 1.42-14.7), respectively.
Elevated levels of IGF-I and IGF-II are associated with risk of SIL while BEMR emerges out to be a derived factor strongly associated with risk of SIL.
PMCID: PMC4800510  PMID: 27042445
Cancer; Cervix; Growth factors
16.  Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study 
British Journal of Cancer  2006;94(2):299-307.
Insulin-like growth factor I (IGF-I) stimulates cell proliferation and can enhance the development of tumours in different organs. Epidemiological studies have shown that an elevated level of circulating IGF-I is associated with increased risk of breast cancer, as well as of other cancers. Most of circulating IGF-I is bound to an acid-labile subunit and to one of six insulin-like growth factor binding proteins (IGFBPs), among which the most important are IGFBP-3 and IGFBP-1. Polymorphisms of the IGF1 gene and of genes encoding for the major IGF-I carriers may predict circulating levels of IGF-I and have an impact on cancer risk. We tested this hypothesis with a case–control study of 807 breast cancer patients and 1588 matched control subjects, nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 23 common single nucleotide polymorphisms in IGF1, IGFBP1, IGFBP3 and IGFALS, and measured serum levels of IGF-I and IGFBP-3 in samples of cases and controls. We found a weak but significant association of polymorphisms at the 5′ end of the IGF1 gene with breast cancer risk, particularly among women younger than 55 years, and a strong association of polymorphisms located in the 5′ end of IGFBP3 with circulating levels of IGFBP-3, which confirms previous findings. Common genetic variation in these candidate genes does not play a major role in altering breast cancer risk in Caucasians.
PMCID: PMC2361124  PMID: 16404426
IGF-I; IGFBP-3; IGFBP-1; IGFALS; single nucleotide polymorphisms; breast cancer
17.  Circulating insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in PSA-detected prostate cancer: the large case control study ProtecT 
Cancer research  2011;72(2):503-515.
Circulating insulin-like growth factor-I (IGF-I) has been studied extensively in prostate cancer, but there is still little information about IGFs and IGF binding proteins (IGFBPs) in cancers detected by the prostate-specific antigen (PSA) test. Here we report the findings of a United Kingdom-based case-control study to investigate circulating IGFs and IGFBPs in PSA-detected prostate cancer with regard to their potential associations with different cancer stages or grades. PSA testing was offered to 110,000 men aged 50-69 years from 2002-2009. Participants with an elevated level of PSA (≥ 3.0 ng/ml) underwent prostate biopsy and measurements of blood serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 obtained at recruitment. We found that serum levels of IGF-II (OR per standard deviation increase: 1.16; 95%CI 1.08,1.24;ptrend<0.001), IGFBP-2 (1.18;1.06,1.31;ptrend<0.01) and IGFBP-3 (1.27;1.19,1.36;ptrend<0.001), but not IGF-I (0.99;0.93,1.04;ptrend=0.62), were associated with PSA-detected prostate cancer. After controlling for IGFBP-3, IGF-II was no longer associated (0.99;0.91,1.08;ptrend=0.62) and IGF-I was inversely associated (0.85;0.79,0.91;ptrend<0.001) with prostate cancer. In addition, no strong associations existed with cancer stage or grade. Overall, these findings suggest potentially important roles for circulating IGF-II, IGFBP-2 and IGFBP-3 in PSA-detected prostate cancer, in support of recent in vitro evidence. While our findings for IGF-I agree with previous results from PSA-screening trials, they contrast with positive associations in routinely-detected disease, suggesting that reducing levels of circulating IGF-I might not prevent the initiation of prostate cancer but might nonetheless prevent its progression.
PMCID: PMC3272440  PMID: 22106399
case-control study; insulin-like growth factors; insulin-like growth factor binding proteins; prostate cancer
18.  IGF-1, IGFBP-1, and IGFBP-3 Polymorphisms Predict Circulating IGF Levels but Not Breast Cancer Risk: Findings from the Breast and Prostate Cancer Cohort Consortium (BPC3) 
PLoS ONE  2008;3(7):e2578.
IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.
PMCID: PMC2440354  PMID: 18596909
19.  Concentrations of IGF-I and IGFBP-3 and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition 
British Journal of Cancer  2012;106(5):1004-1010.
Insulin-like growth factors (IGFs) and their binding proteins (BPs) regulate cell differentiation, proliferation and apoptosis, and may have a role in the aetiology of various cancers. Information on their role in pancreatic cancer is limited and was examined here in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition.
Serum concentrations of IGF-I and IGFBP-3 were measured using enzyme-linked immunosorbent assays in 422 cases and 422 controls matched on age, sex, study centre, recruitment date, and time since last meal. Conditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) adjusted for confounding variables.
Neither circulating levels of IGF-I (OR=1.21, 95% CI 0.75–1.93 for top vs bottom quartile, P-trend 0.301), IGFBP-3 (OR=1.00, 95% CI 0.66–1.51, P-trend 0.79), nor the molar IGF-I/IGFBP-3 ratio, an indicator of free IGF-I level (OR=1.22, 95% CI 0.75–1.97, P-trend 0.27), were statistically significantly associated with the risk of pancreatic cancer. In a cross-classification, however, a high concentration of IGF-I with concurrently low levels of IGFBP-3 was related to an increased risk of pancreatic cancer (OR=1.72, 95% CI 1.05–2.83; P-interaction=0.154).
On the basis of these results, circulating levels of components of the IGF axis do not appear to be the risk factors for pancreatic cancer. However, on the basis of the results of a subanalysis, it cannot be excluded that a relatively large amount of IGF-1 together with very low levels of IGFBP-3 might still be associated with an increase in pancreatic cancer risk.
PMCID: PMC3305958  PMID: 22315049
IGF-I; IGFBP-3; pancreatic cancer; cohort study
20.  IGF1 and IGFBP3 in the Acute Respiratory Distress Syndrome 
Insulin-like growth factor-1 (IGF1) and its most abundant binding protein, insulin-like growth factor binding protein-3 (IGFBP3), have been implicated in fibrotic lung diseases and persistent acute respiratory distress syndrome (ARDS) because of profibrogenic and antiapoptotic activity. Whether levels of circulating IGF1 and IGFBP3 are altered in ARDS, and whether they predict progression of and survival from ARDS remains unknown. This study aims to characterize circulating levels of IGF1 and IGFBP3 in patients at risk for ARDS in relation to (1) development of ARDS, and (2) mortality among ARDS cases.
In this case-cohort study, consecutive patients with risk factors for ARDS admitted to the intensive care unit (ICU) were enrolled and followed prospectively for development of ARDS. Cases were followed for all-cause mortality through Day 60. Of 2397 patients enrolled in the parent study, plasma samples were available in 531 (22%) patients (356 controls, 175 cases) from early in presentation. Total plasma IGF1 and IGFBP3 were measured.
After adjusting for relevant clinical covariates including severity of illness, IGF1 and IGFBP3 levels were significantly lower in ARDS cases than controls (odds ratio [OR], 0.58; P =0.006; OR, 0.57; P=0.0015, respectively). Among ARDS cases, IGF1 and IGFBP3 levels were significantly lower in the 78 (45%) non-survivors (hazard ratio [HR], 0.70; P =0.024; HR, 0.69; P=0.021, respectively).
Lower levels of circulating IGF1 and IGFBP3 were independently associated with ARDS case status. Furthermore, lower levels were associated with mortality among ARDS cases. This data supports a role of the IGF pathway in ARDS.
PMCID: PMC3757506  PMID: 22004906
Adult Respiratory Distress Syndrome; Insulin-Like Growth Factor-1; Insulin-Like Growth Factor Binding Protein-3; Molecular Epidemiology; Serum Biomarkers
21.  Circulating IGF-axis Protein Levels and Their Relation with Levels of Plasma Adipocytokines and Macronutrient Consumption in Women 
Circulating free insulin-like growth factor (IGF)-I and its binding proteins, most notably, IGFBP-1 and IGFBP-2, have been prospectively associated with incident type 2 diabetes in women. However, little is known regarding the factors that may influence these IGF-axis protein levels. To study the relation of IGF-axis protein levels with adipocytokines, macronutrient consumption, and other factors related to diabetes.
Fasting plasma from 558 controls enrolled in a nested case-control study within the Nurses’ Health Study of incident type 2 diabetes in women were tested for: IGF-axis proteins (free and total IGF-I, IGFBP-1, IGFBP-2, IGFBP-3), adipocytokines (leptin, adiponectin, resistin), soluble leptin receptor (sOB-R), inflammatory factors (IL-18 and C-reactive protein (CRP)), insulin, and glycated hemoglobin (HbA1C).
In multivariate models, each 1% increase in sOB-R (mean 34.9 ng/mL, standard deviation (SD) ±11.3) was associated with −0.20% total IGF-I (P=0.0003) and −0.42% free IGF-I (P=0.002), as well as 0.73% higher IGFBP-1 (P<0.0001) and 0.27% IGFBP-2 (P=0.003). For example, a one SD change from the mean sOB-R level was associated with 11% lower free IGF-I. Insulin levels (mean 6.8 μU/mL ±5.3) were inversely and adiponectin (mean 18.3 μg/mL ±7.4) positively associated with IGFBP-1 and IGFBP-2 (all P<0.01). Consumption of dairy protein, monounsaturated fats, and saturated fats, was also correlated with IGF-axis protein levels (all P<0.05).
Several molecular factors and macronutrients were independently associated with plasma IGF-axis protein levels. Which of these, if any, reflect biologic relationships that can be intervened upon to influence IGF-axis protein concentrations warrants further investigation.
PMCID: PMC4190839  PMID: 24888819
IGF-I; free IGF-I; IGFBP-1; IGFBP-2; IGFBP-3; adipocytokines; macronutrients
22.  Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study 
Breast Cancer Research  2007;9(1):R18.
Mammographic density is one of the strongest risk factors for breast cancer and is believed to represent epithelial and stromal proliferation. Because of the high heritability of breast density, and the role of the insulin-like growth factor (IGF) pathway in cellular proliferation and breast development, we examined the association between common genetic variation in this pathway and mammographic density.
We conducted a cross-sectional analysis among controls (n = 1,121) who were between the ages of 42 and 78 years at mammography, from a breast cancer case-control study nested within the Nurses' Health Study cohort. At the time of mammography, 204 women were premenopausal and 917 were postmenopausal. We genotyped 29 haplotype-tagging SNPs demonstrated to capture common genetic variation in IGF1, IGF binding protein (IGFBP)-1, and IGFBP-3.
Common haplotype patterns in three of the four haplotype blocks spanning the gene encoding IGF1 were associated with mammographic density. Haplotype patterns in block 1 (p = 0.03), block 3 (p = 0.009), and block 4 (p = 0.007) were associated with mammographic density, whereas those in block 2 were not. None of the common haplotypes in the three haplotype blocks spanning the genes encoding IGFBP-1/IGFBP-3 were significantly associated with mammographic density. Two haplotype-tagging SNPs in IGF1, rs1520220 and rs2946834, showed a strong association with mammographic density. Those with the homozygous variant genotype for rs1520220 had a mean percentage mammographic density of 19.6% compared with those with the homozygous wild-type genotype, who had a mean percentage mammographic density of 27.9% (p for trend < 0.0001). Those that were homozygous variant for rs2946834 had a mean percentage mammographic density of 23.2% compared with those who were homozygous wild-type with a mean percentage mammographic density of 28.2% (p for trend = 0.0004). Permutation testing demonstrated that results as strong as these are unlikely to occur by chance (p = 0.0005).
Common genetic variation in IGF1 is strongly associated with percentage mammographic density.
PMCID: PMC1851377  PMID: 17300730
23.  Growth hormone and prostate cancer: Guilty by association?1 
Recent case-control studies have found a 7–8% increase in the serum levels of insulin-like growth factor (IGF)-I in patients with prostate cancer (CaP), the most frequently diagnosed cancer in men. We hereby review what is currently known about growth hormone (GH) and the IGF axis in CaP, take a closer inspection of the studies published to date reporting IGF-I levels in CaP patients, and derive implications for the future medical management of patients receiving trophic hormone therapies as well as those at risk for developing CaP. The role of GH in controlling prostate growth and carcinogenesis is still unclear from animal studies and human disease patterns. However, multilayered perturbations of the IGF axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases, such as prostate-specific antigen, have been identified in CaP cells and tissues. Interestingly, IGFBP-3 is a potent inhibitor of prostatic IGF action and also mediates prostate apoptosis via an IGF-independent mechanism. Serum IGFBP-3 levels have been identified to be negatively correlated to the risk of CaP. Notably, GH therapy raises both IGF-I and IGFBP-3 levels in serum. Conclusions based on the studies of IGF-I levels in CaP patients are affected by both the populations studied and the types of IGF-I assay employed. While the studies do indicate an association between serum IGF-I levels and CaP risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for local prostatic IGF-I production. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with CaP. Thus, serum IGF-I may lead to an ascertainment bias among younger men with benign prostatic hyperplasia who are more likely to present with prostatic symptoms and have subclinical CaP diagnosed, Should serum IGF-I levels be proven to play a causal role in the pathogenesis of CaP, interpreting the risk associated with therapies such as GH must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their CaP risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I and IGFBP-3 levels in GH recipients must become standard of care.
PMCID: PMC4152917  PMID: 10442574
Growth hormone; prostate cancer; insulin-like growth factor-1; insulin-like growth factor-binding proteins
24.  Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density 
Increased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a woman's life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here.
Samples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using Taqman (ABI). The main statistical analyses were conducted with the PROC HAPLOTYPE procedure within SAS/GENETICS™ (SAS 9.1.3).
The haplotype analysis revealed six haploblocks within the studied genes. Of those, four had significant associations with circulating levels of IGF1 or IGFBP3 and/or mammographic density. One haplotype variant in the IGF1 gene was found to be associated with mammographic density. Within the IGF2 gene one haplotype variant was associated with levels of both IGF1 and IGFBP3. Two haplotype variants in the IGF2R were associated with the level of IGF1. Both variants of the IGFBP3 haplotype were associated with the IGFBP3 level and indicate regulation in cis.
Polymorphisms within the IGF1 gene and related genes were associated with plasma levels of IGF1, IGFBP3 and mammographic density in this study of postmenopausal women.
PMCID: PMC2853484  PMID: 20302654
25.  Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
Experimental evidence suggests that an overexpression of insulin-like growth factor-I (IGF-I) is implicated in human pancreatic tumors. Increased IGF-II and decreased insulin-like growth factor binding protein-3 (IGFBP-3) serum concentrations have been linked to a number of other cancers.
We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55–74 years of age at baseline, to test whether pre-diagnostic circulating IGF-I, IGF-II, IGFBP-3, andIGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk. Between 1994 and 2006, 187 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n=374), who were alive at the time the case was diagnosed, were selected for each case and matched by age, race, sex and date of blood draw. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for smoking.
IGF-I, IGF-II, and IGFBP-3 concentrations were not significantly associated with pancreatic cancer (highest compared with lowest quartile, OR=1.58, 95% CI 0.91–2.76, p-trend=0.25; OR=0.86, 95% CI 0.49–1.50, p-trend=0.31; and OR=0.88, 95% CI 0.51–1.51, p-trend=0.47, respectively). However, a significant positive trend was observed with high IGF-I/IGFBP-3 molar ratio levels (highest compared with lowest quartile OR=1.54, 95% CI 0.89–2.66, p-trend=0.04).
A higher IGF-I/IGFBP-3 molar ratio represents increased free IGF-I, which maybe a risk factor for pancreatic cancer.
Our results highlight the importance of this biomarker for further investigation in large prospective cohort studies and pooled analysis with other prospective cohorts.
PMCID: PMC2936681  PMID: 20699371
IGF-I; IGF-II; IGFBP-3; IGF-I/IGFBP-3; Pancreatic

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