Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women
ABSTRACT Results from several studies indicate that mammographic density, a strong risk factor for breast cancer, is greater in premenopausal women with higher circulating IGF-I levels. Both mammographic density and circulating IGF-I levels appear to be partly heritable traits. We hypothesized that in premenopausal women, IGF1 variants are associated with circulating IGF-I concentration, which in turn influences variation in breast density. Therefore, we examined the association of IGF1 polymorphisms with circulating IGF-I levels and mammographic density.
Percentage density, amounts of dense and non-dense (fat) tissue, IGF-I levels, and BMI were measured in 163 premenopausal women. Three CA repeat polymorphisms were genotyped, one each at the 5' and 3' ends of IGF1 and one in intron 2.
The number of 19 alleles at the 5' polymorphism was associated with lower circulating levels of IGF-I (P = 0.02), whereas the number of 185 alleles at the 3' polymorphism was associated with higher percentage density (P = 0.03) and a smaller amount of non-dense tissue (P = 0.02). The strength of the effect of the 185 allele at 3' on percentage density was greatly reduced and statistical significance lost when BMI was included in regression models.
Our results suggest an association between the number of 185 alleles at 3' with percentage density. This association appears to be mediated by body composition and particularly body fat, as indicated by the association of 3' IGF1 genotype with non-dense (fat) tissue and the mediating effect of BMI on the association of 3' genotype with percentage density.
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ABSTRACT: High oncogenic risk human papillomaviruses (HPVs) are closely associated with cancer of the cervix. However, HPV infection alone may not be sufficient to cause cervical cancer, and other factors or cofactors may have a cumulative effect on the risk of progression from cervical HPV infection to cancer. The present study investigates the cytosine‑adenine (CA) repeat polymorphism in the P1 promoter region of the insulin‑like growth factor‑1 (IGF‑1) gene among cervical precancerous and cancer patients and healthy control females. The association between these polymorphisms, tissue and blood serum levels of IGF‑1, and cervical cancer risk and progression is evaluated. The material for analysis consisted of blood cells and postoperative tissues from patients diagnosed with low‑grade squamous intraepithelial lesions (L‑SILs), high‑grade squamous intraepithelial lesions (H‑SILs) and invasive cervical cancer (ICC). A polymerase chain reaction amplification and the sequencing of DNA were used for the identification of (CA)n repeats in the IGF‑1 P1 region and detection of HPV DNA. The blood serum concentration of IGF was determined by enzyme‑linked immunosorbent assay. The identification of the IGF‑1 protein in the cervical tissues was performed by immunohistochemical analysis. The range of the length of the CA repeats in the study DNA was 11 to 21. However, the most common allele length and genotype in the control and study patients from serum and tissues was 19 CA repeats and a homozygous genotype of CA19/19. Statistically significant differences in the concentration of IGF‑1 in the blood serum were observed between H‑SILs and controls, only (p=0.047). However, the concentration of IGF‑1 in the group of females with CA19/19, CA19<19 and CA19>19 was significantly higher in the group of patients with H‑SIL (P=0.041) and ICC (P=0.048) in comparison with the control group. An association was detected between CA repeat length <19 and/or >19, IGF concentration in blood serum and tissues and the development of cervical cancer.Molecular Medicine Reports 11/2014; DOI:10.3892/mmr.2014.2916 · 1.48 Impact Factor
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ABSTRACT: A CA-repeat microsatellite in insulin-like growth factor 1 (IGF1) promoter was associated with inter-individual variation of circulating IGF1 level. Previously, we reported that such association was due to variation of haplotype unit in a linkage disequilibrium (LD) block composed of microsatellite and SNPs, suggesting the presence of an interaction between them. In this study, reporter assays were performed to investigate the regulatory effect and interaction of genetic variants on gene expression. We used an in-vitro system to compare the transcriptional activities of haplotypes (rs35767:T>C, the CA-repeat microsatellite, rs5742612:T>C and rs2288377:T>A) in evolutionarily conserved region (ECR) of IGF1 promoter. In haplotype C-T-T, a longer microsatellite had a lower transcriptional activity (17.6±2.4 folds for 17 repeats and 8.3±1.1 folds for 21 repeats), while in haplotype T-C-A, such trend could not be observed, as the microsatellite with 21 repeats had the highest transcriptional activity (17.5±2.3 folds). Because the microsatellite and SNPs affected the transcriptional activity of each other, there may be an interaction between them in the regulation of IGF1 expression. For the first time, we demonstrated that a non-coding microsatellite polymorphism could act as a functional unit and interact with SNPs in the regulation of transcription in human genome. This article is protected by copyright. All rights reserved.Human Mutation 09/2013; 34(9). DOI:10.1002/humu.22363 · 5.05 Impact Factor
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ABSTRACT: Aim: Second-generation antipsychotics (SGA) are known to induce metabolic disturbances. Genetic pathways, such as the IGF pathway could be associated with increased metabolic syndrome (MetS). Additionally, IGF2 methylation varies as a function of environmental influences and is associated with schizophrenia and MetS. The current study aims to evaluate whether genetic and epigenetic variation in genes of the IGF pathway are associated with metabolic disturbances in patients under treatment with SGAs. Methods: Cross-sectional metabolic data from 438 patients with schizophrenia spectrum disorder was analyzed. Using the Sequenom MassARRAY iPLEX(TM) platform, 27 SNPs of the IGF1 and IGF2 genes and the IGF receptors IGF1R and IGF2R were genotyped. Methylation status of seven IGF2 CpG dinucleotides was evaluated using a Sequenom MALDI-TOF spectrometer. Results & conclusion: There was a significant association between IGF2 methylation and genotype, but no significant association between genetic or epigenetic variability and metabolic parameters in the present study. Original submitted 28 October 2013; Revision submitted 7 March 2014.Pharmacogenomics 05/2014; 15(7):951-962. DOI:10.2217/pgs.14.46 · 3.43 Impact Factor