Genetic polymorphisms in IGF-I and IGFBP-3 are associated with prostate cancer in the Chinese population.
ABSTRACT: 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.
Project description:Insulin-like growth factor-1 (IGF-1) plays an important role in the regulation of bone formation and mineralization. We aimed to perform a meta-analysis to assess the association of three IGF-1 single nucleotide polymorphisms (SNPs) rs35767, rs2288377, and rs5742612 with osteoporosis risk.A systematic search of PubMed, Web of Science, Embase, Medline, Scopus, CNKI, and Wanfang databases was conducted. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using a fixed effects model.Four Chinese case-control studies with a total of 2807 participants were included in this meta-analysis. The results revealed an association between rs35767 and osteoporosis risk in all study subjects (women and men) in dominant (OR 1.32, 95% CI 1.13-1.53, P?<?.001), recessive (OR 1.73, 95% CI 1.35-2.21, P?<?.001), homozygote (OR 1.89, 95% CI 1.46-2.45, P?<?.001), and allelic (OR 1.31, 95% CI 1.18-1.47, P?<?.001) models. Subgroup analysis according to gender showed that rs35767 was associated with osteoporosis risk in women under dominant (OR 1.29, 95% CI 1.08-1.54, P?=?.005), recessive (OR 1.59, 95% CI 1.19-2.12, P?=?.002), homozygote (OR 1.73, 95% CI 1.28-2.34, P?<?.001), and allelic (OR 1.28, 95% CI 1.12-1.47, P?<?.001) models. Meta-analysis did not find associations of rs2288377 and rs5742612 with osteoporosis risk. There was no evidence of between-study heterogeneity and publication bias.Our results suggest that rs35767 is associated with osteoporosis risk in Chinese, whereas there is no association of rs2288377 and rs5742612 with osteoporosis risk.
Project description:Osteoporosis is a systemic metabolic and serious skeletal disease commonly observed among the elderly. Insulin-like growth factors (IGFs) are critical regulators for bone cell function. We estimated the role of IGF-I rs35767, rs2288377 and rs5742612 polymorphisms in the susceptibility to osteoporosis in a population of China, and assessed gene-environment interactions. A total of 346 patients with osteoporosis and 346 controls were enrolled. Genotyping of IGF-I rs35767, rs2288377 and rs5742612 was amplified and performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The TA and AA genotypes displayed elevated risk of developing osteoporosis (TA vs TT: OR=1.54, 95% CI=1.11-2.15; AA vs TT: OR=3.65, 95% CI=2.09-6.37). Compared with TT individuals, individuals with the TA+AA genotype had a substantial increased susceptibility to osteoporosis (OR=1.80, 95% CI=1.31-2.46). In recessive model, the AA genotype of rs2288377 displayed 2.89 folds risk of osteoporosis (adjusted OR=2.89, 95% CI=1.70-4.89). A significant negative interaction was found between IGF-I rs2288377 and BMD levels for femoral neck (r=-0.14, P<0.001), total hip (r=-0.09, P<0.001) and trochanter (r=-0.13, P<0.001). In conclusion, we suggest that IGF-I rs2288377 polymorphism had a strong influence on osteoporosis susceptibility in this Chinese population.
Project description:We conducted a case-control study in a Chinese postmenopausal population, and explore the potential role of the promoter region variation of the IGF-1 gene in bone mineral density and osteoporosis risk. 485 postmenopausal women with a primary diagnosis of osteoporosis and 485 age-matched controls were selected between 2012 and 2014. The Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was used for rs35767, rs2288377 and rs5742612 of IGF-1 genotyping. By conditional regression analysis, individuals carrying TT genotype and CT+TT genotype of rs35767 were found to be correlated with an elevated risk of osteoporosis, with adjusted ORs (95% CI) of 1.90 (1.23-2.93) and 1.35 (1.04-1.76), respectively. Our study found that CT+TT genotype of rs35767 was significantly associated with moderate increased risk of osteoporosis in smokers and drinkers, and the ORs (95% CI) were 2.11 (1.06-4.20) and 2.36 (1.29-4.32), respectively. We found that those carrying CT+TT genotype of rs35767 had a significant lower BMD levels at L1-L4 vertebrae, femoral neck, total hip and trochanter compared to those with CC genotype. Our study suggests that TT genotype and CT+TT genotype of IGF-I rs35767 were associated with risk of osteoporosis and BMD levels.
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:This study aimed to explore the association of insulin-like growth factor 1 gene (IGF1) polymorphisms with diabetic retinopathy (DR) in a Chinese Han population.Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping. Genotype frequencies were compared by chi-square test. Odds ratio (OR) with 95% confidence interval (95%CI) was calculated to express the risk intensity of DR. Linkage disequilibrium between IGF1 polymorphisms was analyzed by Haploview. Serum IGF1 concentration was measured by enzyme-linked immunosorbent assays (ELISA) and assessed by student's t test.AG genotype of rs6218 and TT genotype of rs35767 were significantly associated with the elevated risk of DR (rs6218: OR=1.77, P=0.04; rs35767: OR=2.32, P=0.03) and type II diabetes mellitus (T2DM) (rs6218: OR=1.92, P=0.00. rs35767: OR=2.29, P=0.02). Only T allele of rs35767 significantly increased the risk of DR (OR=1.45, P=0.04), however, rs6218 (OR=1.92, P=0.00), rs35767 (OR=0.02, P=0.02) and rs5742612 (OR=2.21, P=0.04) showed obvious association with T2DM. Haplotypes were only associated with T2DM, but not DR. Minor allele homozygote of rs35767 was obviously correlated with serum IGF1 level.IGF1 rs6218 and rs35767 polymorphisms contribute to the risk of DR. IGF1 rs35767 polymorphism may participate in the regulation of serum IGF1 concentration in DR.
Project description: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 2 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.
Project description:The insulin-like growth factor (IGF) axis plays a crucial role in proliferation, differentiation, migration, angiogenesis, and apoptosis. The present study evaluated the associations between IGF axis single-nucleotide polymorphisms (SNPs) and clinical outcomes in advanced gastric cancer (AGC) patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). A total of 190 patients undergoing FOLFOX chemotherapy for AGC were considered eligible for this study. Forty-four SNPs of 10 IGF axis genes were genotyped. Levels of serum IGF1 were measured using enzyme-linked immunoassays. SNPs of the IGF1R (rs12423791), and IGF1 (rs2162679, rs5742612, rs35767) genes were significantly associated with tumor response to FOLFOX. SNPs of rs4619 and rs17847203 were significantly associated with PFS (hazard ratio [HR] 0.575, 95% CI 0.385-0.858, P = 0.007; and HR 2.530, 95% CI 1.289-4.966, P = 0.007; respectively). SNPs of rs2872060 were significantly associated with OS-OS was shorter in patients carrying the TT variant than in those with the GG/GT genotypes (HR, 1.708, 95% CI 1.024-2.850, P = 0.040). The GT genotype of rs12847203 was also identified as an independent prognostic factor (HR 2.087, 95% CI 1.070-4.069, P = 0.031). These results suggest that IGF axis-pathway SNPs could be used as prognostic biomarkers of the outcome of FOLFOX chemotherapy in AGC patients. This information may facilitate identification of population subgroups that could benefit from IGF1R-targeted agents.
Project description: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) >or= 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 (P(adj) = 8.8 x 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 x 10(-3). IGF-I levels were significantly associated with PCa risk (P(trend) = 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.
Project description:BACKGROUND:Increased exposure of colonic and rectal epithelial cells to the promitotic and antiapoptotic effects of insulin and insulin-like growth factors (IGF) is hypothesized to increase colorectal cancer risk. METHODS:In a case-control study nested within the Multiethnic Cohort, we attempted to replicate associations for five genetic variants associated with IGF system biomarkers, insulin, or glucose and to examine their association with the risk of colorectal cancer. In a subset of participants, the association between circulating biomarkers and colorectal cancer risk was examined. Unconditional logistic regression was used to calculate ORs and 95% confidence intervals (CI) for genetic variants (1,954 cases/2,587 controls) and serum biomarkers (258 cases/1,701 controls). RESULTS:Associations with circulating biomarkers were replicated in the Multiethnic Cohort for IGF1 rs35767 and for IGFBP3 rs2854744, rs2854746, and rs3110697 (P < 0.05). Homozygous carriers of the glucokinase regulator (GCKR) rs780094 variant T-allele were at a decreased risk of colorectal cancer (OR, 0.77; 95% CI, 0.64-0.92). In risk factor-adjusted models, participants with the highest prediagnostic IGF-II levels were at an increased risk [OR (T1 vs. T3), 1.58; 95% CI, 1.09-2.28; P(trend) = 0.011] and participants with the highest prediagnostic IGF-binding protein (IGFBP)-3 levels were at a decreased risk of colorectal cancer (OR, 0.53; 95% CI, 0.34-0.83; P(trend) = 0.003). CONCLUSION:These data provide further support for a role of prediagnostic IGF and insulin levels in the etiology of colorectal cancer. IMPACT:Future studies attempting to replicate the association between the GCKR rs780094 variant and the risk of colorectal cancer are warranted.