MicroRNA Binding Site Polymorphisms Research Articles

Importance of STAT3 Polymorphisms on the Risk and Clinical Characteristics of Rheumatoid Arthritis.

Signal transducer and activator of transcription 3 (STAT3) has been introduced as one of the critical genetic factors in the pathogenesis of rheumatoid arthritis (RA). Single nucleotide polymorphisms (SNPs) in microRNA binding sites, known as miRSNPs, are a class of common variants in the 3' untranslated regions of genes targeted by miRNAs. miRSNPs unbalance gene expression by disrupting the binding regions of microRNAs. In this study, we intended to evaluate the association of two miRSNPs with the risk of RA development and its clinical features. We studied 120 Iranian patients with RA and 125 non-RA subjects as controls. The genotypes and alleles of rs1053005 and rs1053023 in each individual were assessed by the high-resolution melting method. The distribution of STAT3 variants did not differ markedly in RA patients compared to healthy controls. Stratification analysis revealed that rs1053005 was linked with a higher concentration of C-reactive protein and an increased erythrocyte sedimentation rate, two indicators of inflammation and disease activity in RA patients. The rs1053023 variant was correlated with higher levels of creatinine as an indicator of renal involvement. Our data demonstrate an association between STAT3 variants and clinical characteristics of RA, such as disease activity and probably kidney impairment. However, we did not observe a significant relationship between the two targeted variants and a predisposition to RA.

A microRNA binding site polymorphism in the 3\u2032 UTR region of VEGF-A gene modifies colorectal cancer risk based on ethnicity: a meta-analysis

BackgroundVascular endothelial growth factor A (VEGF-A) plays an integral role in angiogenesis by contributing to growth, development, and metastasis of solid tumors. Recently, a single-nucleotide polymorphism +936C/T located in the VEGF-A 3′ untranslated region (UTR) facilitated the susceptibility of colorectal cancer. The association between VEGF-A gene polymorphism +936C/T and colorectal cancer risk has been widely studied in the last decade, but presently, the results furnished remain enigmatic. Hence, the study aimed to investigate the association between VEGF-A +936C/T miRNA binding site polymorphism and the risk of developing colorectal cancer.MethodsThis meta-analysis included 13 published case-control studies covering 3465 cases (colorectal cancer) and 3476 healthy controls. Publication bias was examined by means of Begg’s funnel plots and Egger’s regression tests. The quality of the studies included was evaluated using Newcastle-Ottawa scale. Subgroup analyses were performed in accordance to the various ethnicities of the study subjects and the study quality.ResultsFrom the data obtained, it is implied that VEGF-A +936C/T polymorphism did not correlate with elevated colorectal cancer risk in all genetic models. But the results acquired from the subgroup analysis in over dominant model (CT vs. CC + TT: OR = 1.5047, 95% CI = 1.19–1.90) suggest that VEGF-A +936C/T polymorphism leads to the raise in the risk of developing CRC among the East Asian population. No association was observed in Caucasian and South Asian population.ConclusionsOur results indicate that VEGF-A +936C/T polymorphism is not a risk factor for developing CRC in Caucasian and South Asian population. However, the East Asian population was related to an increased risk of developing colorectal cancer due to the presence of the minor allele.

Single nucleotide polymorphisms in microRNA binding sites on the HOX genes regulate carcinogenesis: An in-silico approach

Homeobox proteins, encoded by HOX genes, are transcriptional factors playing a crucial role in the master regulatory pathway in the cells. Any mutations in HOX genes will affect the expression of its allied proteins. Such mutations were correlated to the development of different cancer types. In this study, we found 15 HOX genes with a potential target to miRNA, which regulates the translation of the protein by binding to its mRNA through the 3′UTR region. Single nucleotide polymorphisms (SNPs) in this binding region could drastically affect the protein expression by affecting the number and the stability of miRNA-mRNA complexes. We found 77 miRNAs in 15 genes which were found to have altered binding efficiency because of 26 SNPs. After which, we tried to evaluate the impact of each of these SNPs on related HOX genes. Some SNPs such as SNP 15689 on the HOXB7 gene will decrease gene expression by creating or enhancing new binding sites for miRNA to mRNA, while other SNPs such as SNP 872760 on the HOXB5 gene will overexpress the gene by breaking or decreasing existing binding sites from miRNA to mRNA. Then we conducted an expression analysis to compare the mRNA expression profiles in normal and cancer tissue. Subsequently, we did an enrichment analysis followed by a network analysis to shed light on the metabolic function of the gene that could be affected by mutation and whether these mutations may affect other genes. For the first time, this study delivers information on the possible epigenetic regulation of HOX genes via the 77 miRNAs that have predicted target binding sites on HOX mRNAs, and SNPs may regulate those. Furthermore, we show that the HOX gene misregulation may influence other HOX and non-HOX genes, based on network analysis.

Frequency of MicroRNA Response Elements Identifies Pathologically Relevant Signaling Pathways in Triple-Negative Breast Cancer.

SummaryComplex interactions between mRNAs and microRNAs influence cellular functions. The mRNA-microRNA interactions also determine the post-transcriptional availability of mRNAs and unbound microRNAs. MicroRNAs binds to one or more microRNA response elements (MREs) located on the 3′UTR of mRNAs. In this study, we leveraged MREs and their frequencies in cancer and matched normal tissues to obtain insights into disease-specific interactions between mRNAs and microRNAs. We developed a bioinformatics method “ReMIx” that utilizes RNA sequencing (RNA-Seq) data to quantify MRE frequencies across the transcriptome. We applied ReMIx to triple-negative (TN) breast cancer tumor-normal adjacent pairs and identified MREs specific to TN tumors. ReMIx identified candidate mRNAs and microRNAs in the MAPK signaling cascade. Further analysis of MAPK gene regulatory networks revealed microRNA partners that influence and modulate MAPK signaling. In conclusion, we demonstrate a novel method of using MREs in the identification of functionally relevant mRNA-microRNA interactions in TN breast cancer.

MicroRNA Binding Site Polymorphisms of the Long-Chain Noncoding RNA MALAT1 are Associated with Risk and Prognosis of Colorectal Cancer in Chinese Han Population

Background: The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) gene's rs664589 locus is located within the binding site of the miRNA hsa-miR-194-5p for its cognate long-chain noncoding RNA (lncRNA) MALAT1. The aim of this study was to investigate the association between the rs664589 single nucleotide polymorphism (SNP) and the risk and prognosis of colorectal cancer (CRC) in the Chinese Han population. Methods: A cohort of 340 patients with CRC who underwent surgical resection and another group of 340 healthy subjects were enrolled in this study and analyzed for their rs664589 genotypes. In addition, quantitative real-time-polymerase chain reaction was used to detect the expression levels of the lncRNA MALAT1 and the hsa-miR-194-5p in cancer tissues and paracancerous normal tissues of CRC patients. Results: The risk of CRC in subjects carrying the G allele at the rs664589 locus in the 3' untranslated region of the MALAT1 gene was 1.81 times higher than for C allele carriers. The expression levels of the lncRNA MALAT1 in cancer tissues was significantly higher than that in paracancerous tissues, while the hsa-miR-194-5p expression level was significantly lower in cancerous tissues compared to cognate paracancerous tissues. The progression-free survival (PFS) rate for patients with the MALAT1 gene rs664589 locus GG genotype was significantly lower than that of CG genotype patients. Moreover, lncRNA MALAT1 inhibited the expression of hsa-miR-194-5p. Conclusion: The risk of CRC was relatively higher among MALAT1 rs664589 G allele carriers, and the CRC patients with a G allele had a lower PFS. The likely mechanism underlying these observations is that the rs664589 SNP affects the binding efficiency between the lncRNA MALAT1 and the miRNA has-miR-194-5p, although this awaits laboratory confirmation.

MicroRNA binding site polymorphism in inflammatory genes associated with colorectal cancer: literature review and bioinformatics analysis.

Inflammation, among environmental risk factors, is one of the most important contributors to colorectal cancer (CRC) development. In this way, studies revealed that the incidence of CRC in inflammatory bowel disease patients is up to 60% higher than the general population. MicroRNAs (miRNAs), small noncoding RNA molecules, have attracted excessive attention due to their fundamental role in various aspects of cellular biology, such as inflammation by binding to the 3'-untranslated regions (3'-UTR) of pro and anti-inflammatory genes. Based on multiple previous studies, SNPs at 3'-UTR can affect miRNA recognition elements by changing the thermodynamic features and secondary structure. This effect can be categorized, based on the number of changes, into four groups, including break, decrease, create, and enhance. In this paper, we will focus on functional variants in miRNA binding sites in inflammatory genes, which can modulate the risk of CRC by both investigating previous studies, regarding miRSNPs in inflammatory genes associated with CRC and recruiting in silico prediction algorithms to report putative miRSNPs in 176 inflammatory genes. In our analysis, we achieved 110 miRSNPs in 3'-UTR of 67 genes that seem good targets for future researches.

Association between microRNA binding site polymorphisms in immunoinflammatory genes and recurrence risk of ischemic stroke

MicroRNA binding site polymorphisms in immunoinflammatory genes have been implicated as candidate biomarkers for prediction of complex human diseases. However, the roles of microRNA binding site polymorphisms in stroke onset and prognosis remain unclear. Thus, for the first time, five potential functional polymorphisms in immunoinflammatory genes (CXCR2 rs1126579, TLR4 rs11536889, ADIPOR2 rs12342, MMP-2 rs7201 and MMP-9 rs1056628) were genotyped in 657 patients with ischemic stroke. These five polymorphisms were not related with age onset of ischemic stroke. However, we found that ADIPOR2 rs12342 was significantly associated with a decreased recurrence risk, especially for the patients with small-vessel disease. Moreover, by using multivariate Cox regression, the variant genotype GG/GA of rs12342 was observed as an independent protective factor for stroke recurrence, even after Bonferroni correction. In addition, after the addition of rs12342 in the model with clinical factors, the new model showed the improved discriminatory ability to predict stroke recurrence. In short, our results suggested that ADIPOR2 rs12342 may be a novel genetic biomarker and therapeutic target for ischemic stroke recurrence. Further studies are required to replicate our findings and clarify the potential biological mechanism.

Lack of an Association between a Polymorphism in the KRAS 3′ Untranslated Region (rs61764370) and Endometriosis in a Large European Case-Control Study

Background: Endometriosis is a common disorder that affects 6–10% of reproductive age women. In a previous study, we demonstrated that a polymorphism in let-7 microRNA-binding site in the 3' untranslated region of the KRAS gene was found in 31% of subjects with endometriosis resistant to medical therapy. This polymorphism was now tested in a large, case-control study. Methods: Peripheral blood or peritoneal biopsies from 2,077 European subjects with or without endometriosis and known infertility were tested for the presence of the variant allele using polymerase chain reaction. Results: Histologically proven endometriosis was found in 1,140 subjects, while 937 subjects were disease free. Variant allele carrier rates in subjects with and without endometriosis were 15.7 and 15.1%, respectively. No association between the variant KRAS allele and stage of the disease, age at surgery, body mass index, or type of infertility was identified. Conclusion: A germ-line single-nucleotide polymorphism in the let-7 microRNA-binding site of the KRAS gene was not associated with sporadic endometriosis in an infertile Caucasian population in this large case-control study. However, it remains possible that this gene variant may be a marker of treatment resistance. Further studies on the role of this polymorphism in endometriosis are needed.

Functional Polymorphism Located in the microRNA Binding Site of the Insulin Receptor (INSR) Gene Confers Risk for Type 2 Diabetes Mellitus in the Bangladeshi Population.

Bangladesh has the second largest number of adults with diabetes in South Asia. Compelling evidence suggest that miRNAs contribute to the etiology of Type 2 diabetes mellitus (T2DM) by regulating many aspects of glucose homeostasis. Hence, we hypothesized that genetic polymorphisms in the diabetes-related miRNA target-binding sites could be associated with the risk of T2DM in Bangladesh. The reference Single nucleotide polymorphism (SNP) data from the Insulin Receptor (INSR) gene were downloaded from the ENSEMBL genome browser release 88 and further analyzed in silico for identifying SNPs with deleterious effect and clinical relationships. Further, case-control study using the microRNA-binding site polymorphism rs1366600 (T > C) located at the 3' UTR of the INSR gene was carried out in 217 T2DM patients and 237 healthy controls from Bangladesh. Genotyping was performed using the real time PCR based allele discrimination method. The results showed that the minor allele 'C' is associated with increased risk of T2DM [Odds ratio (OR) 1.87; 95% confidence intervals (CI) 1.28-2.74; P = 0.0010]. When we dissected our analysis to include the dominant model (CC + TC genotype against the TT genotype), we found that the CC and TC genotypes were associated with increased risk of T2DM in Bangladeshi population (OR 2.01; 95% CI 1.31-3.07; P = 0.0012). However, in recessive model (CC vs TT + TC); the effect was not statistically significant (OR 2.23; 95% CI 0.66-7.51; P = 0.1848). Stratification of our data based on the gender of the cases and controls showed similar degree of risk association with respect to different genotypes and alleles. Our study showed that the miRNA binding site polymorphism rs1366600 located at the 3'-UTR region of the INSR gene is associated with increased risk of T2DM in Bangladeshi individuals.

Genotype and allele frequencies of TYMS rs2790 A > G polymorphism in a Chinese paediatric population with acute lymphoblastic leukaemia.

Thymidylate synthase (TYMS) is an important target for methotrexate (MTX). Genetic variations in the TYMS gene contribute to the differences in treatment responses to MTX. The aim of this study was to investigate the distribution of a microRNA (miRNA) binding site polymorphism (rs2790 A>G) in the 3'-untranslated region (3'-UTR) of TYMS and its association with MTX concentration and haematological toxicity in Chinese paediatric patients with acute lymphoblastic leukaemia (ALL). The Sequenom MassARRAY system was used for TYMS rs2790 A>G genotyping in 118 children with ALL. Serum MTX concentrations were measured by a fluorescence polarization immunoassay. Clinical data were extracted from the electronic medical records. The minor allele frequency noted in this study (39.8%) was significantly higher than those in the CEU (Utah residents with northern and western Europe ancestry; 16.2%) and YRI (Yoruba in Ibadan, Nigeria; 25.0%) samples reported in the 1000 Genomes Project (P<.01). The frequency of MTX level >40μmol/L at 24hours in patients with the AA genotype (36.6%) was significantly higher than that in GG genotype carriers (5.9%, P<.05). However, the incidence rates of haematological toxicity were similar in the three genotype groups. Whereas there was evidence of higher blood levels in the A homozygotes, the evidence for this translating to higher toxicity was lacking. A larger study would be required to answer this. The results of this study confirmed the significant ethnic differences in the distributions of the TYMS rs2790 A>G polymorphism. Whereas there was evidence of differences in MTX blood levels according to genotype, our study was not powered to show whether this would lead to more haematological toxicity.

Association between a microRNA binding site polymorphism in SLCO1A2 and the risk of delayed methotrexate elimination in Chinese children with acute lymphoblastic leukemia

Organic anion-transporting polypeptide 1A2 (OATP1A2) is involved in the cellular uptake of methotrexate (MTX). Genetic variation in solute carrier organic anion transporter family member 1A2 (SLCO1A2, the coding gene of OATP1A2) has important implications for the elimination of MTX. We investigated the association between a microRNA (miRNA) binding site polymorphism (rs4149009 G > A) in the 3′-untranslated region (3′-UTR) of SLCO1A2 with the serum MTX concentrations in Chinese children with acute lymphoblastic leukemia (ALL). Genotyping for SLCO1A2 rs4149009 G > A in 141 children with ALL was performed using the Sequenom MassARRAY system. Serum MTX concentrations were determined by fluorescence polarization immunoassay. The percentages of MTX level ≥1 μmol/L at 42 h were compared among the AA, GA, and GG genotypes. The minor allele frequency observed in this study (33.0%) was significantly lower than that in the African samples reported in the 1000 Genomes Project (57.4%, P = 0.00). The incidence rate of delayed MTX elimination was significantly higher in patients with the GG genotype (23.1%) compared with the AA genotype (0.0%, P = 0.03). Bioinformatics tools predicted that the rs4149009 A allele would disrupt the putative binding sites of hsa-miR-324-3p and hsa-miR-1913. These results indicate that the rs4149009 G > A polymorphism might affect MTX pharmacokinetics by interfering with the function of miRNAs.

MicroRNA Binding Site Polymorphisms are Associated with the Development of Gastric Cancer

MicroRNAs (miRNAs) binding to the 3'-untranslated regions (3'-UTRs) of messenger RNAs (mRNAs), affect several cellular mechanisms such as translation, differentiation, tumorigenesis, carcinogenesis and apoptosis. The occurrence of genetic polymorphisms in 3'-UTRs of target genes affect the binding affinity of miRNAs with the target genes resulting in their altered expression. The current case control study of 100 samples (50% cancer patients and 50% health persons as control) was aimed to evaluate the genotyping of microRNA single nucleotide polymorphisms (SNPs) located at the binding site of the 3' UTR of C14orf101 (rs4901706) and mir-124 (- rs531564) genes and their correlations with gastric cancer (GC) development. The Statistical analysis results indicated the significant association of AG development risk with the SNPs located in the 3'-UTR of C14orf101 and mir-124. It could be concluded from the results that these genes are associated with the gastric adenocarcinoma.

Association between MTHFR microRNA binding site polymorphisms and methotrexate concentrations in Chinese pediatric patients with acute lymphoblastic leukemia.

The pharmacokinetics and therapeutic response to methotrexate (MTX) display large variability in the treatment of acute lymphoblastic leukemia (ALL). The aim of the present study was to investigate the association of two microRNA (miRNA) binding site polymorphisms (rs3737966 G>A and rs35134728 DEL/TTC) in the 3'-untranslated region of MTHFR with serum MTX concentrations, in a Chinese pediatric population with ALL. Genotyping for MTHFR rs3737966 and rs35134728 in 144 children with ALL was performed using the Sequenom MassArray system (Sequenom, San Diego, CA, USA). Serum MTX concentrations were measured by a fluorescence polarization immunoassay 24h (C24h ) and 42h (C42h ) after administration. The effects of the polymorphisms on concentration-to-dose (C/D) ratios of MTX were assessed. Complete linkage disequilibrium between rs3737966 and rs35134728 polymorphisms (r2 =1) was found in the study population. The minor allele frequency observed in the present study (17.4%) was significantly lower than those in European and African samples reported in the 1000 Genomes Project (42.9% and 63.9%, respectively; p<0.01). The C/D ratios of MTX at 24 and 42h for the TTC/TTC-A/A haplotype carriers (11.74 and 0.07μmol/l per g/m2 , respectively) were significantly lower than those in DEL/DEL-G/G or DEL/TTC-G/G haplotype carriers (12.49 and 0.09μmol/l per g/m2 , respectively; p<0.05). Computational predictions suggested that the two polymorphisms overlapped with putative binding sites of several miRNAs. The rs3737966 and rs35134728 polymorphisms in MTHFR were associated with serum MTX concentrations. The findings of the present study indicate that miRNAs might be involved in the post-transcriptional regulation of MTHFR.

MicroRNA-binding site polymorphisms in genes involved in colorectal cancer etiopathogenesis and their impact on disease prognosis.

According to the Vogelstein's model of colorectal carcinogenesis, genetic variations in highly penetrant genes may be involved in the colorectal cancer (CRC) pathogenesis. Similarly, aberrant function and/or altered expression of microRNAs (miRNAs) often occur in CRC. In this context, polymorphisms in miRNA-binding sites (miRSNPs) may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and increased susceptibility to common diseases. To explore this phenomenon, we have mined the 3' untranslated regions (3'UTRs) of genes known to be frequently mutated in CRC to search for miRSNPs and tested their association with CRC risk and clinical outcome. Eight miRSNPs (rs1804191, rs397768, rs41116 in APC; rs1137918, s227091, rs4585 in ATM; rs712, rs1137282, rs61764370 in KRAS; rs8674 in PARP1 and rs16950113 in SMAD7) were tested for their association with CRC risk in a case-control study (1111 cases and 1469 healthy controls). The role of these miRSNPs was also investigated in relation to clinical outcome on a subset of patients with complete follow-up. rs8679 within PARP1 was associated with CRC risk and patients' survival. In the dominant model, carriers of at least one C allele were at a decreased risk of cancer (P = 0.05). The CC genotype in rs8679 was also associated with an increased risk of recurrence/progression in patients that received 5-FU-based chemotherapy (log-rank test P = 0.03). Carriers of the homozygous variant genotype TT for rs712 in KRAS gene were associated with a decreased risk of rectal cancer (odds ratio (OR) = 0.65, 95% confidence intervals (CI) 0.43-1.00, P = 0.05) while individuals with colon cancer carrying the heterozygous GT genotype showed a longer overall survival (OS) (P = 0.04). We provide the first evidence that variations in potential miRNA-binding target sites in the 3' UTR of PARP1 gene may modulate CRC risk and prognosis after therapy. Further studies are needed to replicate our finding and assess miRSNPs as predictive biomarkers in independent populations.

1085P - Association of ERP29 genetic polymorphism in microRNA-binding site with oropharynx cancer risk and prognosis

1085P - Association of ERP29 genetic polymorphism in microRNA-binding site with oropharynx cancer risk and prognosis

The Association of MME microRNA Binding Site Polymorphism with the Risk of Late Onset Alzheimer's Disease in Northern Han Chinese.

Although β-amyloid (Aβ) degradation has been normally implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) through cellular biological studies, the genetic studies linking Aβ degradation and LOAD are still scarce. Neprilysin (NEP), one of the most crucial Aβ-degrading enzymes in AD, is the metalloendopeptidase which particularly participates in the monomeric Aβ species degradation. MicroRNAs (miRNAs) exert post-transcriptional dysregulation and their target sequence on the 3' untranslated regions (3'UTR) may be regulated by single nucleotide polymorphisms (SNPs). To investigate the potential risk of common locus within NEP gene (MME) with LOAD in Northern Han Chinese population. We screened a locus (rs6665) in 3' UTR of NEP gene (MME) which sequence was specially regulated by miRNA-187, and further investigated its possible association with LOAD onset in a large case-control study (984 LOAD patients and 1354 healthy controls) in Northern Han Chinese. The distribution of rs6665 genotype (P=0.003) and allele A/C (P=0.001) showed significant difference between LOAD and controls (Odds Ratio (OR) =1.255, 95% Confidence Interval (CI) =1.102-1.429). After adjusting for age, gender and Apolipoprotein (ApoE) ε4 status, the minor C allele of rs6665 showed significant association with LOAD in all three genotypic models (Dominant: P=0.003, OR=1.291, 95%CI=1.092-1.526; Recessive: P=0.030, OR =1.425, 95%CI =1.035- 1.961; Additive: P=0.001, OR=1.249,95%CI=1.093-1.427). After stratifying by ApoE ε4 status, rs6665 polymorphism was found to elevate the LOAD risk in ApoE ε4 carriers (P=0.002, OR=1.846, 95%CI=1.264-2.697). Our study firstly confirmed the association of MME miRNA binding site polymorphism with the risk of LOAD. However, the association results warrant further validation.

From the Viewpoint of Drug Metabolism Research.

Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug response and drug toxicity. Much progress has been made in understanding drug-drug interactions via the inhibition or induction of cytochrome P450s (P450, CYP), as well as the effects of genetic polymorphisms of P450s on pharmacokinetics, and this has facilitated the progress of optimized pharmacotherapy in the clinic. Now, similar information is needed for non-CYP enzymes, especially concerning Phase I enzymes, based on advanced basic and clinical studies. Recently, it was revealed that post-transcriptional regulation by microRNAs or RNA editing plays a significant role in regulating the expression of drug-metabolizing enzymes, thus conferring variability in the detoxification and metabolic activation of drugs or chemicals. Changes in the expression profile of microRNAs in tissues or body fluids can be a biomarker of drug response and toxicity; therefore, such studies could also be useful for drug repositioning. In addition, microRNAs are involved in pharmacogenetics, because single nucleotide polymorphisms in microRNA binding sites of mRNAs, or microRNAs themselves, may cause changes in gene expression. Some microRNA-related polymorphisms could be biomarkers of the clinical outcome of pharmacotherapy. In this review article, recent progress and future directions for drug metabolism studies are discussed.

The association between let-7 microRNA-binding site polymorphism rs712 and cancer risk: a meta-analysis and trial sequential analysis

Background: Previous studies have investigated the relationship between let-7 microRNA-binding site polymorphism rs712 and cancer susceptibility. However, the available conclusions remained inconsistent. The present meta-analysis was thus performed to clarify such associations. Methods: A meta-analysis including 11 studies was performed with 3,572 cases and 4,749 controls. Relevant studies were searched in the databases EMBASE, PubMed and Web of Science, covering relevant papers published until September 1st, 2016. We pooled data with odds ratios (ORs) and 95% confidence intervals (CIs) to assess the strength of the associations. Besides, Begg’s funnel plots and Egger’s regression test were utilized to evaluate publication bias. Furthermore, we took advantage of trial sequential analysis to evaluate whether the evidence of the results was sufficient. Results: Overall, the results showed that significant cancer risk was associated with rs712 for heterozygote model OR =1.10 (95% CI: 1.002–1.22), homozygote model OR =1.71 (95% CI: 1.18–2.49), dominant model OR =1.19 (95% CI: 1.04–1.35), recessive model OR=1.64 (95% CI: 1.17–2.31) and allele model OR =1.21 (95% CI: 1.06–1.39). Moreover, trial sequential analyses for the first time were performed to confirm such associations, demonstrating that the results of our study were based on sufficient evidence. Conclusions: This results of the meta-analysis suggested that rs712 polymorphism was associated with cancer susceptibility, which might act as a potential biomarker for evaluating cancer risk.

Dietary factors and microRNA-binding site polymorphisms in the IL13 gene: risk and prognosis analysis of colorectal cancer.

Long-term dietary intake influences the structure and activity of microorganisms residing in the human gut. The immune response and gut microbiota have a mutual influence on the risk of colorectal cancer (CRC). This study examines the association of gut microbiota–related dietary factors and polymorphisms in the microRNA-binding site of the interleukin 13 gene (IL13) with the risk and prognosis of CRC. Three polymorphisms (rs847, rs848, and rs1295685) were selected for genotyping in a case–control study (513 cases, 572 controls), and 386 CRC patients were followed up. Two dietary factors closely related with gut microbiota (allium vegetables, overnight meal) were significantly associated with CRC development. Although the three SNPs showed no statistically significant associations with the risk and prognosis of CRC, a significant antagonistic interaction was found between rs848 (G–T) and allium vegetable intake (ORi (odds ratio of interaction), 0.92; 95% CI (confidence interval): 0.86, 0.99; P = 0.03); moreover, significant combined and synergistic interactions were observed for all three SNPs and overnight meal intake. This is the first report of significant combined and interactive effects between dietary factors and polymorphisms in the microRNA binding site of IL13 in CRC and may provide direct guidance on intake of allium vegetable and overnight meals for individuals with specific genetic variants of IL13 to modify their susceptibility to CRC.

Polymorphisms in MicroRNA Binding Sites Predict Colorectal Cancer Survival.

Background: MicroRNAs (miRNAs) mediate negative regulation of target genes through base pairing, and aberrant miRNA expression has been described in cancers. We hypothesized that single nucleotide polymorphisms (SNPs) within miRNA target sites might influence clinical outcomes in patients with colorectal cancer.Methods: Sixteen common SNPs within miRNA target sites were identified, and the association between these SNPs and overall survival was assessed in colorectal cancer patients using Kaplan-Meier analysis, Cox regression model, and survival tree analysis.Results: Survival tree analysis identified a higher-order genetic interaction profile consisting of the RPS6KB1 rs1051424 and ZNF839 rs11704 that was significantly associated with overall survival. The 5-year survival rates were 74.6%, 62.7%, and 57.1% for the low-, medium-, and high-risk genetic profiles, respectively (P = 0.006). The genetic interaction profile remained significant even after adjusting for potential risk factors. Additional in silico analysis provided evidence that rs1051424 and rs11704 affect RPS6KB1 and ZNF839 expressions, which in turn is significantly correlated with prognosis in colorectal cancer.Conclusion: Our results suggest that the genetic interaction profiles among SNPs within miRNA target sites might be prognostic markers for colorectal cancer survival.