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.
ABSTRACT 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.
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ABSTRACT: The diagnosis of growth hormone deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding growth hormone (GH1), growth hormone releasing hormone receptor (GHRHR) or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome wide association studies point towards an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis and management of isolated GHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human growth hormone (rhGH) can reverse this effect. Finally the safety of rhGH is currently the subject of much debate and research and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.Endocrine reviews 01/2014; · 19.76 Impact Factor
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ABSTRACT: Objective A polymorphism in the promoter region of the IGF-I gene has been linked to serum IGF-I levels, risk of diabetes and cardiovascular diseases with conflicting results. Aim of this study was to investigate the impact of this polymorphism on the short- (1 yr, n=98) and long- (5 yrs, n=50) term metabolic response to rhGH in GHD adults.Design and Methods Prospective study on GHD adults. Different genotypes were studied by microsatellite method. According to the most frequent 192 bp allele (19 CA-repeats) subjects were divided in homozygous (19/19), heterozygous (19/X) and non-carriers (X/X).Results Basal characteristics of patients as well as their response to rhGH in terms of decrease in BF% and increase in IGF-I levels were not different in the three genotypes groups. Conversely, after 1-year rhGH, a significant worsening of insulin sensitivity (i.e. increase in fasting glucose levels and HOMA-IR) and a significant improvement in lipid profile (i.e. reduction in total- and LDL-cholesterol) was recorded only in homozygous subjects. In the long-term, insulin sensitivity was restored in all the patients, while a significant improvement in lipid profile was observed in homozygous and heterozygous, but not in non-carriers. No difference in rhGH dose among groups was recorded throughout study.Conclusions In GHD adults, the presence of the wild type allele in the IGF-I gene promoter may enhance sensitivity to either negative or positive metabolic changes induced by rhGH.European Journal of Endocrinology 11/2013; · 3.69 Impact Factor
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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; · 1.48 Impact Factor