Interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and between genes and physical activities on physical performance in community-dwelling elders.
ABSTRACT: This study assessed the interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and the interactions of gene and physical activity on handgrip strength, arm muscle mass-adjusted handgrip (armGrip), gait speed (GS), timed up and go (TUG), and leg press strength (LPS). Nine single nucleotide polymorphisms (SNPs) containing three IGF-1 SNPs (rs6214, rs5742692, and rs35767), two AKT2 SNPs (rs892119 and rs35817154), two FOXO1 SNPs (rs17446593 and rs10507486), and two FOXO3 SNPs (rs9480865 and rs2153960) were genotyped in 472 unrelated elders with a mean age of 73.8 years. We observed significant interactions of IGF-1 SNP rs6214 and rs35767 with regular physical activity on TUG and GS; and AKT2 SNP rs892119 and FOXO3 SNP rs9480865 with regular physical activity on armGrip. Genotype GG of IGF-1 rs6214 and rs35767 in individuals without regular physical activity had poor performance in TUG and GS, as well as GG of AKT2 rs892119 decreased armGrip in individuals without regular physical activity. After FDR adjustment, no significant gene-gene interactions were found. A sedentary lifestyle may increase the risk of impairing physical performance and regular physical activity is a remedy for sarcopenia, even a little regular physical activity can overcome carrying some risk alleles in this pathway.
Project description:BACKGROUND Insulin-like growth factor 1 (IGF-1) gene plays an important role in bone and soft tumors. IGF-1 gene polymorphisms have been revealed to be correlated with the carcinogenesis and progression of solid malignancies. We therefore hypothesized that IGF-1 genetic polymorphisms might be associated with the risks and outcomes of osteosarcomas in Chinese individuals. MATERIAL AND METHODS This study included 173 conventional osteosarcoma individuals and 175 tumor-free controls. Five single nucleotide polymorphisms (SNPs) of IGF-1 (rs6214, rs6218, rs35767, rs5742612, and rs5742714) were genotyped. DNA was extracted from peripheral blood and analyzed for SNP genotyping using PCR. RESULTS We found that rs6218 had a predictive role for the susceptibility and progression of osteosarcoma. The presence of TC and CC genotypes of rs6218 indicated higher risk of osteosarcoma. In addition, rs6218 TC and CC genotypes were discovered to be associated with later stage and elevated risk of osteosarcoma metastasis. CONCLUSIONS IGF-1 polymorphisms are potential prognostic predictors of osteosarcoma susceptibility and outcomes.
Project description:PURPOSE: Recent work has suggested that insulin-like growth factor 1 (IGF-1) gene polymorphisms are genetically linked with high-grade myopia (HM), which is a complex-trait eye disorder in which numerous candidate loci and genes are thought to play a role. We investigated whether the IGF-1 single nucleotide polymorphisms (SNPs) rs6214, rs10860860, and rs2946834 are associated with HM (?-6.0 diopters [D]) and any myopia (?-0.5 D) phenotype in Polish families. METHODS: Forty-two multiplex HM Polish families, of whom 127 had HM, participated in the study. All of the family members (n=306) underwent a detailed ophthalmic examination, including axial length measurements. The IGF-1 SNPs rs6214, rs10860860, and rs2946834 were evaluated by PCR-RFLP and direct sequencing methods. Both Family-Based Association Test (FBAT) and family-based Pedigree Disequilibrium Test (PDT) were used to examine the potential association of the IGF-1 SNPs rs6214, rs10860860, and rs2946834 with HM or any myopia. To determine the distribution of the HM-associated SNPs rs6214 and rs10860860, 543 unrelated individuals from the general Polish population were also analyzed. RESULTS: We found no significant association between the IGF-1 SNPs rs6214, rs10860860, and rs2946834 and HM or any myopia phenotype in Polish HM families. In the general Polish population, the minor allele frequencies of the SNPs rs6214 and rs10860860 did not deviate significantly from the distribution reported for European populations (p=0.629). In the FBAT analysis under the dominant model, the haplotype consisted of T allele of rs10860860, with C allele of rs2946834 of IGF-1 was found less frequently transmitted to HM individuals (p=0.0065), pointing to a nonassociated or protective haplotype. CONCLUSIONS: Our results do not support recent studies reporting an association of the SNPs rs6214, rs10860860, and rs2946834 in the IGF-1 gene with HM and any myopia phenotypes. Further replication studies involving other populations are needed to investigate the possible role of IGF-1 as a potential myopia candidate gene.
Project description:INTRODUCTION: Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied. MATERIALS & METHODS: In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression. RESULTS: Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01) and 1.71 (95% CI, 1.10-2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC. CONCLUSION: The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.
Project description:BACKGROUND:The potential association between IGF-1 polymorphisms and high myopia has been investigated in previous studies, but the actual relationship remains controversial. Accordingly, we conducted a meta-analysisincludingcase-control and cohort studies to assess the existing relationship between high myopia and IGF-1 polymorphisms. We searched MEDLINE, EMBASE, and OVID. Odds ratios (OR) with 95% confidence intervals (CI) were derived for single-nucleotide polymorphisms (SNPs) involved in the studies obtained from the retrospective database search. Analyses of heterogeneity, sensitivity, and publication bias were also conducted. The findings from this meta-analysis were based on approximately 2,187 high myopia cases and 1,183 controls, and were used to assess the association between three IGF-1 genetic polymorphisms (rs6214, rs12423791, and rs5742632) and high myopia risks. We investigated the association of the IGF-1 gene SNP rs6214, but no statistical association was observed in the resulting odds ratios (OR) in the allelic (OR = 1.06, 95% CI = 0.89-1.25), dominant (OR = 1.07, 95% CI = 0.90-1.27), or recessive models (OR = 1.06, 95% CI = 0.89-1.26), or in the homozygote (OR = 1.12, 95% CI = 0.91-1.38) and heterozygote comparisons (OR = 1.06, 95% CI = 0.88-1.27). Simultaneously, two other selected SNPs, rs12423791 and rs5742632, were also studied, but similarly, no statistical association existed between these polymorphisms and the risk of high myopia. In conclusions, no statistical association between IGF-1 polymorphisms (rs6214, rs12423791, and rs5742632) and the risk of high myopia was observed following the reported meta-analysis.
Project description:Evidence from human myopia genetic mapping studies (MYP3 locus), modulated animal models, and observations of glycemic control in humans suggests that insulin-like growth factor (IGF)-1 plays a role in the control of eye growth. This study was conducted to determine whether IGF-1 polymorphisms are associated with myopia in a large, international dataset of Caucasian high-grade myopia pedigrees.Two hundred sixty-five multiplex families with 1391 subjects participated in the study. IGF-1 genotyping was performed with 13 selected tag single nucleotide polymorphisms (SNPs) using allelic discrimination assays. A family-based pedigree disequilibrium test (PDT) was performed to test for association. Myopia status was defined using sphere (SPH) or spherical equivalent (SE), and analyses assessed the association of (1) high-grade myopia (<or=-5.00 D), and (2) any myopia (<or=-0.50 D) with IGF-1 markers. Results were declared significant at P<or=0.0038 after Bonferroni correction. Q values that take into account multiple testing were also obtained.In all, three SNPs-rs10860860, rs2946834, and rs6214-were present at P<0.05. SNP rs6214 showed positive association with both the high-grade- and any-myopia groups (P=2x10(-3) and P=2x10(-3), respectively) after correction for multiple testing.The study supports a genetic association between IGF-1 and high-grade myopia. These findings are in line with recent evidence in an experimental myopia model showing that IGF-1 promotes ocular growth and axial myopia. IGF-1 may be a myopia candidate gene for further investigation.
Project description:FOXO3, AKT1 and IGF-2R are critical members of the insulin/IGF-1 signaling pathway. Previous studies showed that polymorphisms (SNPs) in FOXO3, AKT1 and IGF-2R were associated with human longevity in Caucasian population. However, the association of these SNPs in different ethnic groups is often inconsistent. Here, we investigated the association of genetic variants in three genes with human longevity in Han Chinese population. Twelve SNPs from FOXO3, AKT1 and IGF-2R were selected and genotyped in 1202 long-lived individuals (nonagenarians and centenarians) and younger individuals. Rs9486902 of FOXO3 was found to be associated with human longevity in both genders combined in this study (allelic P = 0.002, corrected P = 0.024). The other eleven SNPs were not significantly associated with human longevity in Han Chinese population. The haplotypes TTCTT, CCTTC and CTCCT of FOXO3 as well as GGTCGG and GGTCAG of AKT1 were shown to have a significant difference between case and control (P =0.006, 2.78×10-5, 4.68×10-6, 0.003,0.005, respectively). The estimated prevalence of diabetes and prediabetes in long-lived individuals was significantly lower than in common adult populations (P = 0.001, 2.3×10-26) .Therefore, the search for longevity-associated genes provides the identification of new potential targets beneficial for the treatment of diabetes.
Project description:BACKGROUND:Several studies have been conducted on the relationship between insulin-like growth factor 1 gene (IGF-1) rs35767 polymorphisms and cancer risk, but the results are conflicting. We performed a meta-analysis to investigate the relationship between IGF-1 rs35767 polymorphisms and cancer risk. METHODS:Eight studies (5 for IGF-1 rs35767 C>T and 3 for IGF-1 rs35767 A>G) with a total of 11,257 cases and 16,213 controls were included. The studies were about the association between IGF-1 rs35767 polymorphisms and cancer risk and acquired by searching PubMed, Embase, and Web of Science databases for articles published before January 20, 2019. STATA software was used to analyze the data and identify the strength of the association by using pooled-odds ratios (ORs) with corresponding 95% confidence intervals (CIs). RESULTS:No significant associations were observed between the IGF-1 rs35767 C>T polymorphism and cancer risk in all genetic models. However, the IGF-1 rs35767 A>G polymorphism was significantly associated with increased cancer risk for all genetic models (G vs A: OR?=?1.087, 95% CI: 1.036-1.141, Ph?=?.338; GG vs AA: OR?=?1.272, 95% CI: 1.121-1.442, Ph?=?.359; AG vs AA: OR?=?1.187, 95% CI: 1.043-1.351, Ph?=?.695; AG+GG vs AA: OR?=?1.187, 95% CI: 1.043-1.351, Ph?=?.695; GG vs AA+AG: OR?=?1.086, 95% CI: 1.025-1.151, Ph?=?.275). Begg and Egger tests showed that no publication bias existed. CONCLUSION:Our findings indicated that the IGF-1 rs35767 A>G polymorphism might be a risk factor for cancer development. However, additional well-designed studies with sample sizes larger than ours need to be conducted in the future to verify our findings.
Project description:Background: Skin tags (STs) are benign connective tissue neoplasms, in which insulin-like growth factor -1 (IGF-1) has a mitogenic and antiapoptotic activity. Purpose: We aimed to study for the first time, the possible role of IGF-1 (CA) 19 and rs6214 gene polymorphisms, and its tissue immunoreactivity in the pathogenesis of STs. Patients and methods: This case-control study included 40 ST patients and 20 controls. We searched for (CA) 19 single-nucleotide polymorphism (SNP) using conversional PCR and for rs6214 gene polymorphism using real-time PCR. IGF-1 tissue immunoreactivity was investigated using polyclonal IGF-1 antibody. Results: IGF-1 immunoreactivity showed significantly strong upregulation in epidermis (p=0.002) and dermal components (endothelial cells [p=0.038] and fibroblasts [p=0.004]) of excised STs than control skin. TT and CT rs6214 genotypes and its T allele were significantly associated with STs (p=0.006 and P=0.002, respectively). Also (<192 bp) and 192-194 bp (CA) 19 genotypes were significantly predominant in ST patients than controls (p=0.013). These 4 genotypes were significantly associated with development of multiple STs and epidermal IGF-1 tissue immunoreactivity in studied patients. Conclusions: IGF-1 (CA) 19 and rs6214 gene polymorphisms may contribute to a predisposition of STs in Egyptian patients, the role of which could be mediated through local upregulation of IGF-1 in cutaneous tissues.
Project description:Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) are members of the insulin-like growth factor (IGF) family that play important roles in carcinogenesis. We hypothesized that the functional polymorphisms in IGF-I and IGFBP-3 may be associated with the risk of prostate cancer (PCa) in the Chinese population. This hospital-based case-control study included 664 PCa patients and 702 cancer-free controls. Nine SNPs in IGF-I and IGFBP-3 were genotyped using the TaqMan assay. The genetic associations between the pathogenesis and progression of PCa were assessed by logistic regression. We found that the genotype and allele frequency distribution of rs6218, rs35767 and rs5742612 were significantly different when comparing PCa cases to controls (P ?= 0.005, 0.005 and 0.020, respectively). In the combined analysis, individuals with 2-6 risk alleles had an elevated risk of PCa compared to those with 0-1 risk alleles. We also found that the association between the combined risk alleles and the risk of PCa appeared stronger in the following subgroups: individuals older than 71 years of age (OR ?= 1.41, 95%CI ?= 1.05-1.91, P ?= 0.020), nonsmokers (OR ?= 1.68, 95%CI ?= 1.21-2.32, P ?= 0.002), nondrinkers (OR ?= 1.32, 95%CI ?= 1.02-1.61, P ?= 0.002), and those with a negative family history of PCa (OR ?= 1.28, 95%CI ?= 1.02-1.71, P ?= 0.022). Our results indicate that the three SNPs (rs6218, rs35767 and rs5742612) and the joint genotypes with 2-6 risk alleles, may contribute to the susceptibility to PCa, but not the progression, in the Chinese population.
Project description:OBJECTIVE:It has been shown that Insulin-like growth factor-1 (IGF-1) may be related with bone mineral density (BMD) or osteoporosis. But there are few evidences on the role of genetic variation of IGF-1 on the BMD or osteoporosis. We observed the relationship between polymorphisms of IGF-1(rs35767, rs2288377 and rs5742612) with osteoporosis and BMD in the postmenopausal female population in our study. METHODS:A total of 216 postmenopausal women with a primary diagnosis of osteoporosis and 220 normal healthy women were included in the study. Genomic DNA of IGF-1 rs35767, rs2288377 and rs5742612 was extracted from the whole blood using QIAamp blood DNA mini kits (QIAGEN, Hilden, Germany) according to the methods recommended by the manufacturer. RESULTS:We found that T allele of rs35767 had higher increased risk of osteoporosis (OR=1.34, 95%CI=1.0-1.81). Those carrying T allele of rs35767 had a significant lower BMD at L1-L4 vertebrae, femoral neck, total hip and trochanter when compared with those carrying C allele (P < 0.05). In addition, the BMD of L1-L4 vertebrae, femoral neck, total hip and trochanter decreased by 2.09%, 3.74%, 3.52% and 2.54% in women carrying T alleles compared with those carrying C alleles. CONCLUSION:Our study suggests that polymorphism in IGF-I rs35767 was significantly associated with BMD and osteoporosis in postmenopausal female population, and polymorphism of rs35767 could be a marker for lower BMD and risk of osteoporosis.