Insulin-like growth factor binding protein 3 promoter variant (rs2854744) is associated with nonalcoholic fatty liver disease.

Objective: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and a growing global epidemic. In NAFLD, liver fat surpasses 5% of hepatocytes without the secondary causes of lipid accumulation or excessive alcohol consumption. Given the link between NAFLD and insulin resistance, the possible association between the rs2854744 (-202 G>T) promoter polymorphism of insulin-like growth factor binding protein 3 (IGFBP3) gene and NAFLD was investigated in this study. Materials and methods: In this genetic case-control association study, the IGFBP3 rs2854744 genotypes of 315 unrelated individuals, including 156 patients with biopsy-proven NAFLD and 159 controls, were determined using polymerase chain reaction/restriction fragment length polymorphism analyses. Results: The "GT+TT" genotype of the IGFBP3 rs2854744 polymorphism, compared with the "GG" genotype, was associated with a 2.7-fold increased risk of NAFLD after adjustment for confounding factors (P = 0.009; odds ratio [OR] = 2.71; 95% confidence interval [CI] = 1.19-3.18). Additionally, the IGFBP3 rs2854744 "T" allele, in comparison with the "G" allele, was significantly overrepresented in NAFLD patients than the controls (P = 0.008; OR = 1.85; 95%CI = 1.23-2.94). Conclusion: Our findings first indicated that the IGFBP3 rs2854744 "GT+TT" genotype is a marker of increased NAFLD susceptibility; however, it needs to be supported by further investigations in other populations.

Muscle hypertrophy training does not suppress the GH/IGF axis in young adult males.

PURPOSE: This study aimed to analyze the expression of the IGF type-1 receptor gene (IGF-1r) and IGF-I, GH, testosterone, and IGFBP-3 concentrations in young people subjected to 10 weeks of muscle hypertrophy training. METHODS: IGF-1r expression, serum concentrations of IGF-I, IGFBP-3, GH, and total testosterone, as well as body composition, fat percentage, and body mass index, were determined for 22 healthy young males at three moments of resistance training (first, fifth, and tenth week of training). RESULTS: Throughout the 10 weeks of training, a reduction was observed in the relative expression of the IGF-1r gene (2-ΔΔCT) and an increase in IGF-I and GH concentrations. A reduction in total testosterone concentrations was detected during the recovery period in the fifth week. The IGFBP-3 concentrations did not change throughout the training. CONCLUSIONS: The resistance training protocol prescribed for muscle hypertrophy did not suppress the GH-IGF-I axis, but it did cause alterations in IGF-1r gene expression and in IGF-I kinetics compatible with increased IGF bioactivity.

IGF-1R mRNA expression is increased in obese children.

OBJECTIVES: Obese children are often taller than age-matched subjects. Reports on GH and IGF-I levels in obese individuals are controversial, with normal and reduced GH-IGF-I levels having been reported in this group of patients. Thus, the aim of this study was to analyse insulin-like growth factor type 1 receptor (IGF-IR) mRNA expression in obese children. METHODS: Forty-seven pre-pubertal children were included in this study: 29 were obese and taller than their target height, and 18 were normal eutrophic controls. Fasting blood samples were collected for IGF-IR mRNA expression in isolated lymphocytes and serum IGF-I, ALS, IGFBP-3, and IGFBP-1 concentration analysis. RESULTS: Relative IGF-IR gene expression (2-ΔΔCT) was significantly (P=0.025) higher in obese children (median 1.87) than in controls (1.15). Fourteen of the 29 obese subjects showed 2-ΔΔCT values greater than or equal to 2, while only 2 individuals in the control group showed values above 2 (P=0.01). Obese children showed significantly (P=0.01) higher IGF-I concentrations than the control group (237ng/ml and 144ng/ml, respectively). Among obese patients, 65.5% had IGF-I values above the 75 percentile of the control group (P=0.02). ALS concentration was significantly (P=0.04) higher in the obese group, while IGFBP-3 levels were similar in obese and control children. IGFBP-1 concentration was lower in obese children, while insulin levels and HOMA-IR index were higher than in controls. CONCLUSIONS: The higher IGF-IR mRNA expression observed in obese children, associated with the higher IGF-I and ALS and the lower IGFBP-1 levels, suggest that the higher stature observed in these children may be due to increased IGF-I bioactivity.

Association of IGF-1 CA(n) and IGFBP3 rs2854746 Polymorphisms with Endometrial Polyp Risk.

INTRODUCTION: Insulin-like growth factor 1 (IGF-1) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis. The bioavailability of IGF-1 is regulated by the insulin-like growth factor binding protein 3 (IGFBP3). Genetic variations influence the levels of IGF-1 and IGFBP3. The purpose of this study was to examine the association of polymorphisms IGF-1 CA(n) and IGFBP3 rs2854746 with risk of endometrial polyps. MATERIALS AND METHODS: Case control observational study, composed of 104 women with antecedent of endometrial polyp (case group) and 81 postmenopausal women without antecedent of endometrial diseases (control group). Genotyping of IGF-1 CA(n) was performed by PCR and fragment analysis by capillary electrophoresis, and genotyping of IGFBP3 rs2854746 was performed by PCR-HRM. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. RESULTS: The genotype IGF-1 CA(19)/CA(19) was associated with an increased endometrial polyp risk (OR=2,57; IC 95%= 1,09 - 6,01); this was also found when combining it with CA(>19)/CA(n) genotypes (OR=2,18; IC 95%= 1,06-4,47). The IGFBP3 rs2854746 analyses showed the CG genotype having a protective effect for endometrial polyp (OR=0,37; IC 95%= 0,19-0,73), fact also observed when grouping CG and GG carriers (OR=0,51; IC 95%= 0,28-0,93). CONCLUSION: The genotypes CA(19)/CA(19) and CA(19)/CA(19) + CA(>19)/CA(n) of the IGF-1 CA(n) may be considered a risk for endometrial polyp, whereas the genotypes CG and CG + GG of IGFBP3 rs2854746 polymorphism have an inverse effect of endometrial polyp risk.

Insulin-like growth factor-I serum levels and their biological effects on Leishmania isolates from different clinical forms of American tegumentary leishmaniasis.

BACKGROUND: American tegumentary leishmaniasis (ATL) in Brazil is mostly caused by Leishmania (Viannia) braziliensis, with known forms of the disease being cutaneous (CL), mucosal (ML) and disseminated (DL) leishmaniasis. The development of the lesion in ATL is related both to the persistence of the Leishmania in the skin and to the parasite-triggered immune and inflammatory responses that ensue lesions. In this context one factor with expected role in the pathogenesis is insulin-like growth factor (IGF)-I with known effects on parasite growth and healing and inflammatory processes. In the present study, we addressed the effect of IGF-I on intracellular amastigote isolates from CL, ML and DL patients within human macrophage and we evaluated the IGF-I and IGF-binding protein-3 (IGFBP3) serum levels in patients presenting different clinical forms and controls from the endemic area. METHODS: We evaluated biological variability in the responses of intracellular amastigotes of Leishmania isolates derived from CL, ML, and DL patients from an area for ATL in response to IGF-I. Intracellular amastigote growth was evaluated using the human macrophage cell line THP-1. Arginase activity in infected cells was evaluated quantifying the generated urea concentration. Serum samples from patients and controls were assayed using chemiluminescent immunometric assay to determine IGF-I and IGFBP3 levels. RESULTS: We observed an increase in intracellular parasitism upon IGF-I stimulus in 62.5 % of isolates from CL, in 85.7 % from ML and only 42.8 % from DL cases. In DL, the basal arginase activity was lower than that of CL. We then evaluated the IGF-I and IGFBP3 serum levels in patients, and we observed significantly lower levels in ML and DL than in CL and control samples. CONCLUSIONS: The data suggest that IGF-I is modulated distinctly in different clinical forms of tegumentary leishmaniasis. IGF-I seemingly exerts effect on parasite growth likely contributing to its persistence in the skin in earlier phase. In addition the decreased IGF-I serum levels may affect the modulation of inflammation and lesion healing in chronic phase. In view of potential role of IGF-I in the pathogenesis of ATL we can speculate on therapeutic procedures taking into account the local IGF-I level.

Relationship between vitamin D receptor (VDR) polymorphisms and the efficacy of recombinant human growth hormone (rhGH) treatment in children with idiopathic short stature.

Polymorphisms in the vitamin D receptor (VDR) gene are associated with idiopathic short stature (ISS) in several countries. This study aimed to identify a possible correlation between polymorphisms in the VDR promoter in Chinese children with ISS and the efficacy of the recombinant human growth hormone (rhGH) treatment. Pre-pubertal children with ISS and healthy age- and gender-matched children (N = 95 each) were enrolled in this study. Two single nucleotide polymorphisms (SNPs) in the VDR promoter (rs11568820 at the Cdx-2-binding site upstream of exon 1e and rs4516035 at -1012 upstream of exon 1a) were typed. The growth velocity, standard deviation score (SDS) of height for chronological age, height SDS for bone age, predicted adult height, and serum insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) levels of the ISS patients were determined before and 6 months after rhGH treatment. No significant differences were observed in the genotype frequencies between the ISS cases and controls. After rhGH treatment, the growth velocity of the A/G genotype at the Cdx-2-binding site SNP locus was significantly higher than that of the G/G genotype; the IGF-1 and IGFBP-3 levels were also higher in the treated group than the untreated group. However, these changes were independent of the VDR-promoter genotype. Polymorphisms in the VDR promoter may not result in the pathogenesis of ISS in Chinese children. The A/G genotype showed a significantly higher growth velocity than the G/G genotype, and may represent a short-term marker of growth potential.

IGFBP-3 A-202C and C2133G polymorphisms and colorectal cancer risk: a meta-analysis of case-control studies.

Recent evidence suggests that genetic variations in the IGFBP-3 gene may impact susceptibility to colorectal cancer, but individually published results are inconclusive. Our meta-analysis was aimed at providing a more precise estimation of these associations. An extensive literature search was conducted for appropriate articles published before May 1, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratios (OR) with 95% confidence interval (CI) were calculated. Eleven case-control studies were included with a total of 11,895 colorectal cancer patients and 17,147 healthy controls. Our meta-analysis indicated that the G variant of IGFBP-3 C2133G polymorphism may be associated with increased colorectal cancer risk. However, no statistically significant association was noted between IGFBP-3 A-202C polymorphism and colorectal cancer risk. No publication bias was detected in this meta-analysis. The current meta-analysis suggests that the IGFBP-3 C2133G polymorphism may confer susceptibility to colorectal cancer. The G variant of the IGFBP-3 C2133G polymorphism may serve as a useful biomarker for predicting the risk of colorectal cancer.

Influence of growth hormone receptor (GHR) exon 3 and -202A/C IGFBP-3 genetic polymorphisms on clinical and biochemical features and therapeutic outcome of patients with acromegaly.

BACKGROUND: The association of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms with clinical presentation, biochemical measurements and response to therapies in acromegaly have been suggested. OBJECTIVE: To evaluate the presence of these polymorphisms in acromegaly and their influence on clinical and laboratorial characteristics of patients at diagnosis and after treatment in a large cohort of acromegalic patients. PATIENTS AND METHODS: This is a cross-sectional study developed in a single tertiary reference center. Clinical data were obtained from the medical records of 186 acromegalic patients (116 women, age range 21-88 years). GH and IGF1 levels and GHR-exon 3 and -202 A/C IGFBP3 polymorphisms were evaluated in the same hospital. RESULTS: At diagnosis, serum GH concentrations were lower in patients with GHR-d3 genotype than those with GHR-fl, whereas an association of lower IGFBP3 levels with d3 allele was observed only after neurosurgical or medical treatments. However, these associations were not confirmed in posterior statistical analysis. CONCLUSION: Our results suggest that GHR-exon 3 and -202 A/C IGFBP3 polymorphisms did not show any consistent association on clinical and laboratorial features of acromegalic patients even after treatment.

PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells.

Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.

Insulin-like growth factor binding protein-3 (IGFBP-3) genetic variant and the risk of esophageal squamous cell carcinoma in a Chinese population.

Insulin-like growth factor binding protein-3 (IGFBP-3) exerts anti-proliferative or pro-apoptotic effects through IGF-dependent as well as IGF-independent mechanisms in vitro. The purpose of this study was to examine the association between genetic variants in IGFBP-3 (rs2270628) and the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese Han population. Five hundred ESCC cases and 500 cancer-free controls of the Chinese Han population were involved in this study. The IGFBP-3 single-nucleotide polymorphism (SNP) rs2270628 was genotyped and the estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for its association with the risk of ESCC were determined using unconditional logistic regression analysis. Compared with the rs2270628 CC genotype, TT genotype was associated with a significantly increased ESCC risk with OR (95%CI) of 2.07 (1.05-4.09), but CT genotype was not (OR = 1.25, 95%CI =0.94-1.66). IGFBP-3 SNP rs2270628 may contribute to the risk of ESCC in the Chinese Han population.

Cellular proliferation rate and insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-3 and estradiol receptor alpha expression in the mammary gland of dairy heifers naturally infected with gastrointestinal nematodes during development.

Mammary ductal morphogenesis during prepuberty occurs mainly in response to insulin-like growth factor-1 (IGF-1) and estradiol stimulation. Dairy heifers infected with gastrointestinal nematodes have reduced IGF-1 levels, accompanied by reduced growth rate, delayed puberty onset, and lower parenchyma-stroma relationship in their mammary glands. Immunohistochemical studies were undertaken to determine variations in cell division rate, IGF-1 system components, and estradiol receptors (ESR) during peripubertal development in the mammary glands of antiparasitic-treated and untreated Holstein heifers naturally infected with gastrointestinal nematodes. Mammary biopsies were taken at 20, 30, 40, and 70 wk of age. Proliferating cell nuclear antigen immunolabeling, evident in nuclei, tended to be higher in the parenchyma of the glands from treated heifers than in those from untreated. Insulin-like growth factor binding proteins (IGFBP) type 2 and type 3 immunolabeling was cytoplasmic and was evident in stroma and parenchyma. The IGFBP2-labeled area was lower in treated than in untreated heifers. In the treated group, a maximal expression of this protein was seen at 40 wk of age, whereas in the untreated group the labeling remained constant. No differences were observed for IGFBP3 between treatment groups or during development. Immunolabeling for α ESR (ESR1) was evident in parenchymal nuclei and was higher in treated than in untreated heifers. In the treated group, ESR1 peaked at 30 wk of age and then decreased. These results demonstrate that the parasite burden in young heifers negatively influence mammary gland development, affecting cell division rate and parameters related to estradiol and IGF-1 signaling in the gland.

Circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-binding protein-3, genetic polymorphisms and mammographic density in premenopausal Mexican women: results from the ESMaestras cohort.

The insulin-like growth factor (IGF) axis plays an essential role in the development of the mammary gland. High circulating levels of IGF-I and of its major binding protein IGFBP3 have been related with increased mammographic density in Caucasian premenopausal women. Some common single nucleotide polymorphisms (SNPs) in genes of the IGF pathway have also been suggested to play a role in mammographic density. We conducted a cross-sectional study nested within the large Mexican ESMaestras cohort to investigate the relation between circulating levels of IGF-I, IGFBP-3, the IGF-I/IGFBP-3 ratio, five common SNPs in the IGF-1, IGFBP-3 and IGF-1R genes and mammographic density in 593 premenopausal Mexican women. Mean age at mammogram was 43.1 (standard deviation, SD = 3.7) years, and average body mass index (BMI) at recruitment was 28.5 kg/m(2). Mean percent mammographic density was 36.5% (SD: 17.1), with mean dense tissue area of 48.3 (SD: 33.3) cm(2) . Mean IGF-I and IGFBP-3 concentrations were 15.33 (SD: 5.52) nmol/l and 114.96 (SD: 21.34) nmol/l, respectively. No significant associations were seen between percent density and biomarker concentrations, but women with higher IGF-I and IGF-I/IGFBP-3 concentrations had lower absolute dense (p(trend) = 0.03 and 0.09, respectively) and nondense tissue areas (p(trend) < 0.001 for both parameters). However, these associations were null after adjustment by BMI. SNPs in specific genes were associated with circulating levels of growth factors, but not with mammographic density features. These results do not support the hypothesis of a strong association between circulating levels of growth hormones and mammographic density in Mexican premenopausal women.

Expression levels of mRNA for insulin-like growth factors 1 and 2, IGF receptors and IGF binding proteins in in vivo and in vitro grown bovine follicles.

This study investigated mRNA levels for insulin-like growth factors (IGFs) IGF1 (IGF-I) and IGF2 (IGF-II), IGF receptors (IGF1R and IGF2R), and binding proteins (IGFBP-1, IGFBP-2. IGFBP-3, IGFBP-4, IGFBP-5 and IGFBP-6) in bovine follicles of 0.2, 0.5 or 1.0 mm in diameter. mRNA expression levels in in vitro cultured follicles that reached approximately 0.5 mm were compared with that of in vivo grown follicles. IGF1R and IGF2R expression levels in 0.5 mm in vivo follicles were higher than in 1.0 or 0.2 mm follicles, respectively. IGFBP-1, IGFBP-2. IGFBP-3, IGFBP-4, IGFBP-5 and IGFBP-6 showed variable expression in the follicular size classes analyzed. In vitro grown follicles had significantly reduced expression levels for IGF1, IGF1R, IGFBP-3, IGFBP-5 and IGFBP-6 mRNA when compared with 0.2 mm follicles, but, when compared with in vivo grown follicles (0.5 mm), only IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-6 showed a reduction in their expression. In conclusion, IGFs, their receptors and IGFBPs showed variable expression of mRNA levels in the follicular size classes analyzed.

Dynamic transcriptional regulation of autocrine/paracrine igfbp1, 2, 3, 4, 5, and 6 in the skeletal muscle of the fine flounder during different nutritional statuses.

The IGF-binding proteins (IGFBPs) play a dual role in the regulation of the activity and bioavailability of IGFs in different tissues. Diverse evidence has shown that IGFBPs can inhibit and/or potentiate IGF actions. In this study, igfbp1, 2, 3, 4, 5, and 6 were isolated in the fine flounder, a flat fish species that shows slow growth and inherent Gh resistance in muscle. Subsequently, the expression of all igfbps was assessed in the skeletal muscle of flounder that underwent different nutritional statuses. igfbp1 was not expressed in muscle during any of the nutritional conditions, whereas igfbp3 and igfbp5 were the lowest and the highest igfbps expressed respectively. A dynamic expression pattern was found in all the igfbps expressed in skeletal muscle, which depended on the nutritional status and sampling period. During the fasting period, igfbp2, 4, and 5 were downregulated, whereas igfbp3 was upregulated during part of the fasting period. The restoration of food modulated the expression of the igfbps dynamically, showing significant changes during both the long- and short-term refeeding. igfbp3 and igfbp6 were downregulated during short-term refeeding, whereas igfbp5 was upregulated, and igfbp2 and igfbp4 remained stable. During long-term refeeding, the expression of igfbp2, 4, 5, and 6 increased, while igfbp3 remained unchanged. In conclusion, this study shows for the first time the isolation of all igfbps in a single fish species, in addition to describing a dynamic nutritional and time-dependent response in the expression of igfbps in the skeletal muscle of a nonmammalian species.

The interactive effect of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on rhGH responsiveness and treatment outcomes in patients with Turner syndrome.

CONTEXT: There is great interindividual variability in the response to recombinant human (rh) GH therapy in patients with Turner syndrome (TS). Ascertaining genetic factors can improve the accuracy of growth response predictions. OBJECTIVE: The objective of the study was to assess the individual and combined influence of GHR-exon 3 and -202 A/C IGFBP3 polymorphisms on the short- and long-term outcomes of rhGH therapy in patients with TS. DESIGN AND PATIENTS: GHR-exon 3 and -202 A/C IGFBP3 genotyping (rs2854744) was correlated with height data of 112 patients with TS who remained prepubertal during the first year of rhGH therapy and 65 patients who reached adult height after 5 ± 2.5 yr of rhGH treatment. MAIN OUTCOME MEASURES: First-year growth velocity and adult height were measured. RESULTS: Patients carrying at least one GHR-d3 or -202 A-IGFBP3 allele presented higher mean first-year growth velocity and achieved taller adult heights than those homozygous for GHR-fl or -202 C-IGFBP3 alleles, respectively. The combined analysis of GHR-exon 3 and -202 A/C IGFBP3 genotypes showed a clear nonadditive epistatic influence on adult height of patients with TS treated with rhGH (GHR-exon 3 alone, R² = 0.27; -202 A/C IGFBP3, R² = 0.24; the combined genotypes, R² = 0.37 at multiple linear regression). Together with clinical factors, these genotypes accounted for 61% of the variability in adult height of patients with TS after rhGH therapy. CONCLUSION: Homozygosity for the GHR-exon3 full-length allele and/or the -202C-IGFBP3 allele are associated with less favorable short- and long-term growth outcomes after rhGH treatment in patients with TS.

Growth hormone pharmacogenetics: the interactive effect of a microsatellite in the IGF1 promoter region with the GHR-exon 3 and -202 A/C IGFBP3 variants on treatment outcomes of children with severe GH deficiency.

Insulin-like growth factor type 1 (IGF1) is a mediator of growth hormone (GH) action, and therefore, IGF1 is a candidate gene for recombinant human GH (rhGH) pharmacogenetics. Lower serum IGF1 levels were found in adults homozygous for 19 cytosine-adenosine (CA) repeats in the IGF1 promoter. The aim of this study was to evaluate the influence of (CA)n IGF1 polymorphism, alone or in combination with GH receptor (GHR)-exon 3 and -202 A/C insulin-like growth factor binding protein-3 (IGFBP3) polymorphisms, on the growth response to rhGH therapy in GH-deficient (GHD) patients. Eighty-four severe GHD patients were genotyped for (CA)n IGF1, -202 A/C IGFBP3 and GHR-exon 3 polymorphisms. Multiple linear regressions were performed to estimate the effect of each genotype, after adjustment for other influential factors. We assessed the influence of genotypes on the first year growth velocity (1st y GV) (n=84) and adult height standard deviation score (SDS) adjusted for target-height SDS (AH-TH SDS) after rhGH therapy (n=37). Homozygosity for the IGF1 19CA repeat allele was negatively correlated with 1st y GV (P=0.03) and AH-TH SDS (P=0.002) in multiple linear regression analysis. In conjunction with clinical factors, IGF1 and IGFBP3 genotypes explain 29% of the 1st y GV variability, whereas IGF1 and GHR polymorphisms explain 59% of final height-target-height SDS variability. We conclude that homozygosity for IGF1 (CA)19 allele is associated with less favorable short- and long-term growth outcomes after rhGH treatment in patients with severe GHD. Furthermore, this polymorphism exhibits a non-additive interaction with -202 A/C IGFBP3 genotype on the 1st y GV and with GHR-exon 3 genotype on adult height.

Urinary bladder cancer risk in relation to a single nucleotide polymorphism (rs2854744) in the insulin-like growth factor-binding protein-3 (IGFBP3) gene.

Currently, twelve validated genetic variants have been identified that are associated with urinary bladder cancer (UBC) risk. However, those validated variants explain only 5-10% of the overall inherited risk. In addition, there are more than 100 published polymorphisms still awaiting validation or disproval. A particularly promising of the latter unconfirmed polymorphisms is rs2854744 that recently has been published to be associated with UBC risk. The [A] allele of rs2854744 has been reported to be associated with a higher promoter activity of the insulin-like growth factor-binding protein-3 (IGFBP3) gene, which may lead to increased IGFBP-3 plasma levels and cancer risk. Therefore, we investigated the association of rs2854744 with UBC in the IfADo case-control series consisting of 1,450 cases and 1,725 controls from Germany, Hungary, Venezuela and Pakistan. No significant association of rs2854744 with UBC risk was obtained (all study groups combined: unadjusted P = 0.4446; adjusted for age, gender and smoking habits P = 0.6510), besides a small effect of the [A] allele in the Pakistani study group opposed to the original findings (unadjusted P = 0.0508, odds ratio (OR) = 1.43 for the multiplicative model) that diminished after adjustment for age, gender and smoking habits (P = 0.7871; OR = 0.93). Associations of rs2854744 with occupational exposure to urinary bladder carcinogens and smoking habits were also not present. A meta-analysis of all available case-control series including the original discovery study resulted in an OR of 1.00 (P = 0.9562). In conclusion, we could not confirm the recently published hypothesis that rs2854744 in the IGFBP3 gene is associated with UBC risk.

Gene expression in swine granulosa cells and ovarian tissue during the estrous cycle.

The components of the insulin-like growth factor (IGF) system appear to be involved in regulation of ovarian follicular growth and atresia in the pig. We investigated the expression pattern of mRNAs for IGF1 (IGF1), its binding proteins (IGFBP1, IGFBP2, IGFBP3, and IGFBP5), and epidermal growth factor in swine follicle cells and ovarian tissue throughout the estrous cycle using the real-time quantitative PCR technique. The results of gene expression were analyzed using linear regression with gene expression as a dependent variable and days of estrous cycle as an independent variable. Additionally, an analysis was made of the correlation of expression levels with plasma concentration of follicle-stimulating hormone, luteinizing hormone, estradiol-17ß, progesterone, and prolactin. Expression of mRNA of all of these genes was detected in granulosa cells and ovarian tissue. IGFBP3 mRNA showed a quadratic expression pattern (P ≤ 0.001) and was significantly and positively correlated with progesterone (r = 0.81; P ≤ 0.01) but negatively correlated with prolactin (r = -0.596; P ≤ 0.05). Expression of the other genes was unaffected by the stage of the estrous cycle. Real-time quantitative PCR effectively detected all transcripts, including the very low levels of IGFBP1 transcripts, and could be used for studies of follicle dynamics.

Influence of insulin-like growth factor-binding proteins-2 and -3 in the pathogenesis of cystic ovarian disease in cattle.

Ovarian cysts are one of the major causes of infertility in dairy cows. The development is associated with an endocrine imbalance in the hypothalamo-hypophyseal-gonadal axis in which endocrine factors participate in follicular growth and differentiation and in the secretion of ovarian hormones. Insulin-like growth factor family are essential local regulators of ovarian follicle development and functionality and actions are mediated by binding protein activity. The aim of the present study was to analyze the expression of IGFBP-2 and IGFBP-3 in developing follicles of normal estrous cycling animals and with spontaneous and induced cystic ovarian disease (COD) to determine IGF bioavailability. The mRNA of IGFBP-2 and IGFBP-3 in follicular walls was quantified by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. Protein expression was analyzed by immunohistochemistry. The results demonstrated reduced amounts of mRNA of both IGFBPs in the granulosa cells of ovarian follicles of animals with COD (P<0.05). The present study suggests that the IGF system or imbalances between IGFs and IGFBPs may be involved in COD of cattle.