Rs1799983 Polymorphism Research Articles

Association of endothelial nitric oxide synthase (NOS3) gene polymorphisms with primary open-angle glaucoma in a Saudi cohort

AimTo investigate the association of endothelial nitric oxide synthase (NOS3) gene polymorphisms in patients with primary open-angle glaucoma (POAG) of Saudi origin.MethodsThis case-control study included 173 patients with POAG (94 men and 79 women) and 171 controls (98 men and 73 women). Genotyping of rs2070744 (T-786C) and rs1799983 (G894T) variants of the NOS3 gene was performed using TaqMan® assay.ResultsRs1799983 genotypes showed a significant association with POAG but did not survive Bonferroni correction (pcorrection = 0.01). The minor ‘T’ allele was significantly associated with the risk of POAG among men (p = 0.025, odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.07–2.94). Likewise, the genotypes were significantly associated with POAG among men in dominant (p = 0.030, OR = 1.92, 95% CI = 1.06–3.48) and log-additive models (p = 0.022, OR = 1.82, 95% CI = 1.08–3.07), and after adjustment for age and smoking. Genotype and allele frequencies of rs2070744 were not significantly different between POAG cases and controls, and after sex stratification. CG haplotype was significantly protective (p = 0.011, OR = 0.52, 95% CI = 0.32–0.87) and CT haplotype conferred significantly increased risk of POAG (p = 0.016, OR = 2.60, 95% CI = 1.16–5.82) among men. Rs1799983 showed trend (p = 0.054) towards risk of POAG independent of age, gender, smoking, and rs2070744 polymorphism in logistic regression analysis. Both the polymorphisms showed no association with POAG phenotypes such as intraocular pressure and cup/disc ratio.ConclusionOur results suggest that the polymorphism rs1799983 and the haplotypes of rs20707440 and rs1799983 in the NOS3 gene may significantly modulate the risk of POAG in Saudi’s, particularly among men. Further larger studies are needed to confirm these findings.

Rs10757274 gene polymorphisms in coronary artery disease: A systematic review and a meta-analysis.

Background:It has been reported the rs10757274 SNP (present on locus 9p21 in the gene for CDKN2BAS1) might be associated with susceptibility to coronary artery disease (CAD). Owing to mixed and inconclusive results, we conducted a meta-analysis to investigate the association between rs10757274 polymorphism and the risk of CAD.Objectives:The present study aimed to investigate the relationship between rs10757274 polymorphism and the risk of CAD.Methods:All studies of the rs10757274 SNP with CAD that were published between 2007 and 2018 were retrieved from the PubMed database. Meta-analysis was performed with Stata 14.0 software. The effect size of the rs10757274 SNP with CAD risk was assessed based on the odds ratios (ORs) with calculation of 95% confidence interval (CI).Results:Eleven studies including 52,209 subjects (cases: 7990, controls: 44,219) were included in the final data combination. Pooled overall analyses showed that rs10757274 (allele model: P < .001; dominant model: P < .001; recessive model: P < .001; Heterozygote codominant: P = .002; Homozygote codominant: P < .001) polymorphisms were significantly associated with the likelihood of CAD. Significant heterogeneity between individual studies appears in all 5 models. Further subgroup analyses revealed that rs10757274 polymorphisms were all significantly correlated with the likelihood of CAD and no heterogeneity were observed in West Asians.Conclusions:Our findings indicated that rs10757274 polymorphisms may serve as genetic biomarkers of CAD, especially in West Asians.

The role of serum E-selectin level and E-selectin gene S128R polymorphism on theenlargement of renal cyst in patients withpolycystic kidney disease: Geneticbackground of renal cyst growth .

To determine the role of E-selectin gene S128R polymorphism on the enlargement of renal cysts in patients with polycystic kidney disease (PKD). 76 PKD patients with no comorbidity were enrolled in the study. Serum E-selectin levels were analyzed by enzyme-linked immunoabsorbent assay (ELISA). E-selectin gene S128R (561 A>C, rs: 5361) polymorphism was examined by polymerase chain reaction restriction fragment length (PCR-RFLP). Magnetic resonance imaging was performed at baseline evaluation and at the end of the 1st year to determine cyst enlargement and total kidney volume (TKV). No significant difference was identified between AA genotype and AC or CC variants of E-selectin gene S128R polymorphism in terms of age, disease duration, baseline cyst volume, cyst volume at the 12th month, baseline dominant cyst volume, and dominant cyst volume at the 12th month. In contrast, a significant difference was determined between the groups with regard to the change of TKV (2.9±13.4 vs. 5.2±16.3 mm3; respectively, p = 0.01). In the correlation analysis, the serum E-selectin level was significantly correlated to glucose, alanine transaminase, creatinine, calcium, phosphorus, total protein, albumin, and end diastolic volume (p = 0.0001, p = 0.001, p = 0.03, p = 0.021, p = 0.023, p = 0.002, p = 0.003, and p = 0.047, respectively). Multivariate logistic regression analysis demonstrated a 1.32-fold higher risk of cyst enlargement in patients with CC polymorphism when compared to AA genotype (p = 0.052), but not between AA and AC genotypes or CC and AC genotypes. PKD patients with CC variants of the E-selectin gene S128R polymorphism are at greater risk of cyst enlargement. The results of the present study should be confirmed with further studies with large sample size and longer duration of follow-up.

The Association of Serum Clusterin Levels and Clusterin Rs11136000 Polymorphisms with Alzheimer Disease in a Turkish Cohort

Objectives: Several large-scale genome association studies have shown that variants in the “Clusterin”' (CLU) gene are important risk factors for Alzheimer's disease (AD). It has also been shown that plasma CLU levels were elevated in patients with AD and associated with disease severity and progression. In this study, we aimed to investigate whether the CLU rs11136000 polymorphism was associated with AD in our cohort of Turkish patients. We also evaluated the association of serum CLU levels and rs11136000 genotypes between patients and controls. Materials and Methods: Genotyping was performed in 327 patients who were diagnosed as having AD (mean age: 67.2 ± 10.8 years) and 344 controls (mean age: 57.7 ± 13.1 years). The rs11136000 genotypes were determined using quantitative real-time polymerase chain reaction with hydrolysis probes. Serum CLU levels were assessed in 25 patients with AD and 10 controls using enzyme-linked immunosorbent assay. Results: Our results showed no significant difference in genotype and allele frequencies of CLU rs11136000 polymorphisms between patients with AD and controls. Serum CLU levels in patients with AD did not differ from those of the controls. Furthermore, serum CLU levels showed no major difference between carriers of CC and TT + CT genotypes in the controls and patients with AD. Conclusion: Our results suggest that the CLU rs11136000 polymorphism is not associated with AD in our Turkish patients, and rs11136000 genotypes may not have an effect on serum CLU levels.

Genetic Markers at ANRIL, FTO and 2q36.3 Locus in Czech Patients Undergoing Coronary Artery Bypass Graft Surgery

Coronary artery bypass graft (CABG) surgery is one of the most commonly performed operations worldwide. We compared genotype frequencies of three major cardiovascular disease (CVD)-associated genetic markers (ANRIL, FTO and 2q36.3 locus) between 753 patients who underwent CABG at the Institute for Clinical and Experimental Medicine (Prague, Czech Republic) and 2,559 controls from the Czech post-MONICA study. Subjects with at least one major A allele in the rs10757274 polymorphism (ANRIL) were more prevalent in patients after CABG than in the controls (81.7 % vs 72.7 %; OR [95 % CI] 1.67 [1.35-2.05]; P &lt; 0.0001). In contrast, variants within the FTO gene (OR 0.87; 95% CI, 0.70-1. 09 in a TT vs. GG comparison, P = 0.24) and 2q36.3 locus (OR 1.16; 95% CI, 0.98-1.37 in a +A vs. CC comparison, P = 0.08) were not significantly associated with CVD in our study. Variants were not associated with anthropometric, biochemical, or clinical characteristics within the patient group. Our study suggests that patients with CABG are more commonly carriers of some but not all CVD-associated alleles.

Epistasis of polymorphisms related to the articular cartilage extracellular matrix in knee osteoarthritis: Analysis-based multifactor dimensionality reduction.

Osteoarthritis (OA) is a complex disease with a multifactorial etiology. The genetic component is one of the main associated factors, resulting from interactions between genes and environmental factors. The aim of this study was to identify gene-gene interactions (epistasis) of the articular cartilage extracellular matrix (ECM) in knee OA. Ninety-two knee OA patients and 147 healthy individuals were included. Participants were genotyped in order to evaluate nine variants of eight genes associated with ECM metabolism using the OpenArray technology. Epistasis was analyzed using the multifactor dimensionality reduction (MDR) method. The MDR analysis showed significant gene-gene interactions between MMP3 (rs679620) and COL3A1 (rs1800255), and between COL3A1 (rs1800255) and VEGFA (rs699947) polymorphisms, with information gain values of 3.21% and 2.34%, respectively. Furthermore, in our study we found interactions in high-risk genotypes of the HIF1AN, MMP3 and COL3A1 genes; the most representative were [AA+CC+GA], [AA+CT+GA] and [AA+CT+GG], respectively; and low-risk genotypes [AA+CC+GG], [GG+TT+GA] and [AA+TT+GA], respectively. Knowing the interactions of these polymorphisms involved in articular cartilage ECM metabolism could provide a new tool to identify individuals at high risk of developing knee OA.

Possibilities of using the rs2070744 polymorphism of the endothelial nitric oxide synthase gene for the identification of severe coronary atherosclerosis in young and middle-aged patients with myocardial infarction

Possibilities of using the rs2070744 polymorphism of the endothelial nitric oxide synthase gene for the identification of severe coronary atherosclerosis in young and middle-aged patients with myocardial infarction

Association between vascular endothelial growth factor gene polymorphisms and PCOS risk: a meta-analysis.

Vascular endothelial growth factor (VEGF) plays important roles in the pathogenesis of polycystic ovary syndrome (PCOS). Several single nucleotide polymorphisms (SNP) of the VEGF gene have been identified and are associated with the aberrant secretion of VEGF protein. This meta-analysis aimed to evaluate the impact of the VEGF +405G>C (rs2010963), -460C>T (rs833061) and -2578A>C (rs699947) polymorphisms on PCOS susceptibility. A systematic search of the Embase, PubMed, Web of Science and Wanfang databases was carried out to identify relevant studies published before 19 July 2019. Seven eligible studies were included in this meta-analysis involving 1100 patients with PCOS and 1141 control individuals. The pooled analysis revealed no significant association between PCOS risk and the +405G>C (rs2010963), -460C>T (rs833061) or -2578A>C (rs699947) polymorphisms in women. Subgroup analysis by ethnicity indicated that Asian women carrying the VEGF +405C allele had a lower risk of PCOS (C versus G: odds ratio [OR] 0.731, 95% confidence interval [CI] 0.544-0.982, P < 0.05, I2 = 46.4%; CG versus GG: OR 0.667, 95% CI 0.469-0.948, P < 0.05, I2 = 18.4%; CC versus GG: OR 0.611, 95% CI 0.390-0.958, P < 0.05, I2 = 24.3%). The study demonstrates that for all women regardless of ethnicity, no significant associations between VEGF SNP and PCOS were observed; however, +405G>C (rs2010963) may protect Asian women from PCOS.

The roles of ANRIL polymorphisms in coronary artery disease: a meta-analysis.

Background: The relationship between antisense non-coding RNA (ncRNA) in the INK4 locus (ANRIL) polymorphisms and coronary artery disease (CAD) remains inconclusive. Thus, we conducted this meta-analysis to better evaluate the roles of ANRIL polymorphisms in CAD. Methods: Systematic literature search of PubMed, Medline, and Embase was performed to identify potential relevant articles. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association. Results: Fifteen studies were finally enrolled for analyses. Overall analyses suggested that rs1333040 (dominant model: P<0.0001; recessive model: P<0.0001; allele model: P<0.0001), rs1333049 (dominant model: P=0.02; allele model: P=0.02) and rs2383207 (additive model: P=0.004) polymorphisms were significantly associated with the risk of CAD. Further subgroup analyses showed that rs1333040, rs1333049, and rs2383207 polymorphisms were significantly correlated with the risk of CAD in East Asians, rs2383206 and rs10757274 polymorphisms were significantly correlated with the risk of CAD in West Asians, while rs2383206, rs10757274, and rs10757278 polymorphisms were significantly correlated with the risk of CAD in Caucasians. Conclusion: Our findings indicated that rs1333040, rs1333049, rs2383206, rs2383207, rs10757274, and rs10757278 polymorphisms might serve as genetic biomarkers of CAD in certain ethnicities.

Examination of Paraoxonase 1 Gene Polymorphism in Cases with Chronic Otitis Media

Objective: Chronic otitis media (COM) is a multifactorial disorder, the pathogenesis of which has yet to be fully elucidated. Numerous aetiological factors, including genetics, eustachian tube dysfunction, autoimmunity, infection, osteoclastic activity, cytokines, endotoxins, and products of lipid peroxidation resulting from oxidative stress, have been proposed to explain the chronic inflammation which lies at the heart of the disorder. The aim of this study is to investigate a possible relationship between the pathogenesis of COM and polymorphism within the paraoxonase 1 (PON1) gene. Methods: We investigated 49 patients admitted to the Otorhinolaryngology Department and diagnosed with COM between September and November 2017. The control group consisted of 51 healthy individuals. Polymerase chain reaction (PCR) – restriction fragment length polymorphism (RFLP) methods were used to genotype the PON1 Q192R (rs662) polymorphism. Results: When the case and control groups were compared in terms of the existence of PON1 (Q192) polymorphism, there was no statistically significant difference between the groups (p=0.166, p>0.05). When intergroup comparison was performed on the type of PON1 (Q192) polymorphism, there was also no statistically significant difference (p=0.261, p>0.05). Conclusion: The present study is the first known study in which PON1 polymorphism has been examined in cases of COM. The results of our study failed to indicate a statistically significant relationship between PON1 polymorphism and COM. However, it is important to note that the higher rate of 192RR polymorphism within the control group control may indicate a protective effect in COM.

GCH1 (rs841) polymorphism in the nitric oxide-forming pathway has protective effects on obstructive sleep apnea

Several studies have recently investigated the contribution of genetic factors in obstructive sleep apnea (OSA). Patients with OSA suffer from a reduction in nitric oxide (NO) serum level. This study investigated rs841, A930G p22phox, and rs1799983 polymorphisms in three critical genes involved in NO formation. A total of 94 patients with OSA and 100 healthy controls were enrolled into the study. Results showed there was no association between rs841, A930G p22phox and rs1799983 polymorphism and the risk of OSA (P = 0.51, P = 0.4 and P = 0.33, respectively). Moreover, rs841 GA genotype had a reverse relationship with the severity of OSA (P = 0.005). On the other hand, rs841 GA and A930G p22phox AA genotypes had a protective effect on daytime sleepiness in OSA patients (P = 0.01and P = 0.02, respectively). Additionally, the combination of rs841 and A930G p22phox (AG/AG and AG/AA) genotypes was significantly associated with a reduction in daytime sleepiness in OSA patients (P = 0.03 and P = 0.03, respectively). According to the results of our study, GA genotype of rs841 and GA/AA genotypes of A930G p22phox polymorphisms significantly reduced the severity of the problem and daytime sleepiness in OSA patients.

Associations between twelve common gene polymorphisms and susceptibility to hepatocellular carcinoma: evidence from a meta-analysis

BackgroundAssociations between polymorphisms in vitamin D receptor (VDR)/vascular endothelial growth factor (VEGF)/interleukin-18 (IL-18)/mannose-binding lectin (MBL) and susceptibility to hepatocellular carcinoma (HCC) were already explored by many studies, yet the results of these studies were inconsistent. The aim of this meta-analysis was to better clarify associations between polymorphisms in VDR/VEGF/IL-18/MBL and HCC by combing the results of all relevant studies.MethodsEligible publications were searched from PubMed, Embase, WOS, and CNKI. We used Review Manager to combine the results of individual studies.ResultsThirty studies were included in this study. Combined results revealed that VDR rs7975232, VDR rs2228570, VEGF rs699947, VEGF rs3025039, IL-18 rs1946518, and MBL rs7096206 polymorphisms were all significantly associated with HCC in the overall pooled population. We also obtained similar significant associations for VDR rs7975232, VDR rs2228570, IL-18 rs1946518, and MBL rs7096206 polymorphisms in Asians.ConclusionsCollectively, this meta-analysis proved that VDR rs7975232, VDR rs2228570, VEGF rs699947, VEGF rs3025039, IL-18 rs1946518, and MBL rs7096206 polymorphisms may confer susceptibility to HCC in certain populations.

The evaluation of VEGF and HIF-1α gene polymorphisms and multiple sclerosis susceptibility.

Multiple sclerosis (MS) is an autoimmune disease that leads to myelin sheath destruction. Hypoxia-inducible factor 1 (HIF-1) has several roles in cells, such as inducing inflammation and angiogenesis. Recently, several lines of evidence have indicated the role of the hypoxia response and the HIF-1 signaling pathway in an autoimmune disease such as MS. The present study aimed to evaluate the effects of HIF-1α gene polymorphisms and vascular endothelial growth factor (VEGF) (as a major target gene of HIF-1α) gene polymorphism on MS susceptibility. In total, 150 MS patients and 150 healthy age- and gender-matched people as a control group participated in the present study. The polymerase chain reaction-restriction fragment length polymorphism method was used for genotyping. The results obtained showed that the CC genotype of the VEGF rs699947 polymorphism was significantly higher in the case group than in the control group (p = 0.004). Also, we showed a significant relationship between the VEGF rs699947 polymorphism and MS in a dominant inheritance model (p = 0.005). Regarding the VEGF rs699947 polymorphism allelic distribution, the C allele frequency was significantly higher in the control group than in the case group (71.3% versus 61%, respectively, p = 0.009) and decreased the MS susceptibility by 1.6-fold (odds ratio = 1.6, 95% confidence interval = 1.2-2.2). There was no significant difference between the two groups with respect to HIF-1α rs11549465 genotypic distribution. The HIF-1α C111A polymorphism was non-polymorphic in our study population, except in the case group where nine subjects carried the CA genotype. We show a significant association between VEGF rs60047 polymorphism and MS susceptibility. However, our results do not show a significant association between MS and HIF-1α polymorphisms.

A meta-analysis of the relationship between paraoxonase 1 polymorphisms and cancer

Some previous studies already explored associations between paraoxonase 1 (PON1) polymorphisms and cancer, with conflicting findings. Here, we aimed to better analyse the relationship between PON1 polymorphisms and cancer in a larger combined population by performing a meta-analysis. We searched PubMed, Embase, and Web of Science for related articles. We calculated odds ratio (OR) and 95% confidence interval (CI) to estimate whether there are genetic associations between PON1 polymorphisms and cancer. Forty studies were included for this meta-analysis. The PON1 rs854560 polymorphism (L55M) was found to be significantly associated with cancer in general population (dominant comparison: p = .04, OR = 0.85, 95%CI 0.73–0.99; recessive comparison: p = .007, OR = 1.27, 95%CI 1.07–1.51; allele comparison: p = 0.02, OR = 0.85, 95%CI 0.75–0.97). Subgroup analyses indicated that the significant findings were mainly driven by the haematological tumours and breast cancer subgroups. We did not observe any positive findings for PON1 rs662 polymorphism (Q192R) in combined analyses. In summary, this meta-analysis proved that PON1 rs854560 polymorphism could be used to identify individual with elevated susceptibility to cancer, especially for haematological tumours and breast cancer.

Role of matrix metalloproteinase-9 gene polymorphisms in glaucoma: A hospital-based study in Chinese patients.

BackgroundGlaucoma is the irreversible vision loss and contributes second leading cause of blindness worldwide. Matrix metalloproteinase‐9 (MMP‐9) is involved with remodeling and destruction of extracellular matrix. Elevated MMP‐9 levels and various functional variants of MMP‐9 have been associated with glaucoma in different population. In the current investigation, we tested association of MMP‐9 common variants with different clinical categories of glaucoma in Chinese population.Materials and MethodsWe enrolled total of 396 glaucoma patients those reported to hospital comprising of 212 primary angle closure glaucoma (PACG) cases and 184 primary open‐angle glaucoma POAG patients. In addition, 329 normal individuals from similar geographical areas were enrolled as healthy controls. Five common single nucleotide polymorphisms (rs3918242, rs3918254, rs2250889, rs3918249, and rs17576) were genotyped by PCR‐RFLP. Plasma levels of MMP‐9 were quantified by ELISA.ResultsHeterozygotes (GC) and allele “G” for rs2250889 polymorphism were more frequent in PACG cases compared with healthy controls (GC: P < .0001, OR = 2.26; G: P < .0001, OR = 1.19). Similarly, heterozygous mutant and minor allele for rs3918242 polymorphism were more prevalent in POAG in comparison with healthy controls. Interestingly, distribution of rs17576 variant was statistically higher in both PACG and POAG cases than healthy controls. Furthermore, analysis of plasma MMP‐9 with MMP‐9 polymorphisms revealed significant association of rs2250889, rs3918242, and rs17576 with plasma levels of the protein.ConclusionsMMP‐9 mutants are associated with elevated plasma MMP‐9 and predisposed to development of glaucoma.

Genetic polymorphism of eNOS (G894T) gene in insulin resistance in type 2 diabetes patients of Pakistani population

Insulin resistance associated with type 2 diabetes (T2DM) consequences in the development of metabolc syndrome. Due to the complex mechanism, various pathogenic factors like enviromental and genetic predispositon contribute to the disease pathogenicity. The reduced availability of eNOS has been determined as a mark of insulin resistance pathogenesis. The objctive of this study was to investigate genetic polymorphism of eNOS (rs1799983; G894T) with susceptibility of insulin resistance in type 2 diabetes (T2DM) patients from Pakistani population. Total of 322 (161 T2DM cases and 161 healthy controls) subjects were recruited for this study. Genomic DNA extraction was carried out by standard phenol-chloroform protocols. PCR amplification of the unique oligonucleotides of eNOS gene was done and restriction fragment analysis (RFLP) was performed by site-specific enzyme BanII. The frequency of GG (wild genotype) was higher (77.6%) in cases than in controls (47.2%), heterozygous GT genotype higher in controls than patients (OR = 0.26, p < 0.0005 and after adjustment, OR = 0.34, p = 0.091). Different genetic models like dominant model of GTT OR 0.29, p = 0.038 respectively) and log-additive model indicated the significant protective effect of the genotype before and after adjustment for the confounding factors. This study demonstrates that there is no association between eNOS rs1799983 polymorphism and insulin resistance in T2DM patients of Pakistani population.

406O - VEGFR2 and ITGA polymorphisms as novel predictors of therapeutic response and toxicities for pediatric and young adult sarcoma undergoing anti-angiogenic therapy

BackgroundThe impact of germline mutations of the angiogenesis pathways on the therapeutic response has been extensively studied for the carcinoma population. However, such information is almost unknown for pediatric and young adult’s sarcoma, for which the field has seen the rapid growing popularity of the use of the anti-angiogenic therapy. MethodsIn this study, we retrospectively analyzed 79 tissue sarcoma patients less than 45 yrs receiving anti-angiogenic therapy (apatinib). In 67 (84%) of these patients, twenty previously reported single nuclear polymorphism (SNPs) in angiogenesis pathway were genotyped to screen for potential toxicity and predictive biomarkers. ResultsThe mean 6 mo PFS rate was 64%, with the duration of response varying from no response to more than 26 months. Multivariate analysis indicated that hand-foot reactions, hair depigmentation and spontaneously pneumothorax (SP) remain independent toxicity biomarker for greater PFS. Interestingly, we observed a strong correlation of ITGA2 rs1126643 polymorphism vs surgical wound complications (C/C 4% vs C/T 24% vs T/T 33%, p = 0.008) as well as SP (C/C 13.8% vs C/T 36.4% vs T/T 66%), suggesting that Integrin mechanism might underline both toxicities. Moreover, VEGFR2 rs2071559 polymorphism remains the only sensitivity biomarker for mPFS (mutation vs WT, 12 mo vs 5 mo), regardless of the sarcoma subtypes. Surprisingly, such mutations were to be associated with the incidence of hair depigmentation (R = 0.398, p = 0.026), further supporting that hair discoloration is a mechanism-based toxicity biomarker. Moreover, a significant higher frequecies of such two mutations (0.53 for ITGA polymorphism, 0.59 for VEGFR2 polymorphism) in our cohort than general Han Chinese (1000G project database) suggest a theoretical impact on the sarcomagenesis. ConclusionsOur study is the first one examining the angiogenesis germline polymorphism for the younger population in bone and soft tissue cancer. VEGFR2 (rs2071559) as well as ITGA (rs1126643) might serve as pan-sarcoma biomarkers for VEGFR2 targeted therapy and warrant further validation for its biological and clinical implications. Legal entity responsible for the studyRuijin Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

MicroRNA-binding site polymorphisms and risk of colorectal cancer: A systematic review and meta-analysis.

Genetic variations in miRNAs binding site might participate in cancer risk. This study aimed to systematically review the association between miRNA‐binding site polymorphisms and colorectal cancer (CRC). Electronic literature search was carried out on PubMed, Web of Science (WOS), Scopus, and Embase. All types of observational studies till 30 November 2018 were included. Overall 85 studies (21 SNPs) from two systematic searches were included analysis. The results showed that in the Middle East population, the minor allele of rs731236 was associated with decreased risk of CRC (heterozygote model: 0.76 [0.61‐0.95]). The minor allele of rs3025039 was related to increased risk of CRC in East Asian population (allelic model: 1.25 [1.01‐1.54]). Results for rs3212986 were significant in overall and subgroup analysis (P < .05). For rs1801157 in subgroup analysis the association was significant in Asian populations (including allelic model: 2.28 [1.11‐4.69]). For rs712, subgroup analysis revealed a significant (allelic model: 1.41 [1.23‐1.61]) and borderline (allelic model: 0.92 [0.84‐1.00]) association in Chinese and Czech populations, respectively. The minor allele of rs17281995 increased risk of CRC in different genetic models (P < .05). Finally, rs5275, rs4648298, and rs61764370 did not show significant associations. In conclusion, minor allele of rs3025039, rs3212986, and rs712 polymorphisms increases the risk of CRC in the East Asian population, and heterozygote model of rs731236 polymorphism shows protective effect in the Middle East population. In Europeans, the minor allele of rs17281995 may increase the risk of CRC, while rs712 may have a protective effect. Further analysis based on population stratifications should be considered in future studies.

1697P - VEGFR2 and ITGA polymorphisms as novel pan-sarcoma biomarkers for sensitivity prediction as well as toxicity prevention anti-angiogenesis therapy in pediatric and young adult patients

BackgroundThe impact of germline mutations of the angiogenesis pathways on the therapeutic response has been extensively studied for the carcinoma population. However, such information is almost unknown for pediatric and young adult sarcoma, for which the field has seen the rapid growth the use of the anti-angiogenic therapy. MethodsIn this study, we retrospectively analyzed 79 tissue sarcoma patients less than 45 yrs old receiving anti-angiogenic therapy (apatinib). In 67 (84%) of these patients, twenty previously reported single nuclear polymorphism (SNPs) in the angiogenesis pathway were genotyped to screen for potential toxicity and predictive biomarkers. ResultsThe mean 6mo PFS rate was 64%, with the duration of response varying from no response to more than 26 months. Multivariate analysis indicated that hand-foot reactions, hair depigmentation and spontaneously pneumothorax (SP) remain independent toxicity biomarkers for greater PFS. Interestingly, we observed a strong correlation of ITGA2 rs1126643 polymorphism vs surgical wound complications (C/C 4% vs C/T 24% vs T/T 33% , p=0.008) as well as SP (C/C 13.8% vs C/T 36.4% vs T/T 66%), suggesting that integrin mechanisms might underle both toxicities. Moreover, VEGFR2 rs2071559 polymorphism remains the only sensitivity biomarker for mPFS (mutation vs WT, 12mo vs 5mo), regardless of the sarcoma subtypes. Suprisingly, such mutations were associated with the incidence of hair depigmentation (R=0.398, p=0.026), further supporting that hair discoloration is a mechanism-based toxicity biomarker. Moreover, significantly higher frequencies such mutations (0.53 for ITGA polymorphism, 0.59 for VEGFR2 polymorphism) were seen in our cohort than the general Han Chinese (1000G project database) suggesting a theoretical impact on the sarcomagenesis. ConclusionsOur study is the first one examining the angiogenesis germline polymorphism for the younger population in bone and soft tissue cancer. VEGFR2 (rs2071559) as well as ITGA (rs1126643) might serve as pan-sarcoma biomarkers for VEGFR2-targeted therapy and warrant further validation for its biological and clinical implications. Legal entity responsible for the studyRuijin Hospital, Orthopaedic Oncology Group. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Association between Vascular Endothelial Growth Factor Plasma Levels and rs699947 Polymorphism and Coronary Collateral Vessel Formation

Background: The vascular endothelial growth factor (VEGF), as an angiogenic cytokine, binds endothelial cell receptors and stimulates angiogenesis and collateral formation. We evaluated the association between VEGF plasma levels and the gene polymorphism rs699947 and the formation of coronary collaterals in patients with coronary artery disease. Methods: A total of 195 patients with ≥70% narrowing in at least 1 coronary vessel (according to coronary angiography) were included in the study. The presence of the rs699947 polymorphism within the promoter of the VEGF gene was investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The plasma VEGF concentration was quantified via the ELISA method. The Rentrop method was used to grade the extent of collateral development. Results: There was no significant difference in VEGF levels between the groups with good and poor collaterals. The frequency of the A allele of rs699947 was found to be higher in the patients with good collaterals than in those with poor collaterals (P=0.014). The odds ratio of good collaterals for AA was 2.67 (P=0.025) when compared with the CC genotype. Further, our additive model revealed an association between the rs699947 polymorphism and collateral formation (OR: 1.96, 95% CI: 1.05-3.65, P=0.033). Conclusion: The rs699947 polymorphism might be a novel genetic factor affecting collateral development in Iranian patients with coronary artery disease.