Single Nucleotide Polymorphisms Rs3746444 Research Articles

Identification of Breast Cancer Associated Putative Functional Single Nucleotide Polymorphisms in the Iranian Population through In Silico Analyses

Previous studies have found several distinct alleles at both levels of transcriptional activity and protein-DNA binding manners in breast cancer patients vs. healthy individuals through multi-step experimental approaches. This study presents a computational-based model to investigate the regulatory potential and functional properties of disease-related non-coding single nucleotide polymorphisms (SNPs) variants through several online in silico tools in the Iranian population. The association between the risk of breast cancer and its putative single nucleotide polymorphisms in the Iranian population was investigated through SNPedia database and genome-wide association studies (GWAS). Furthermore, a meta-analysis was performed by Comprehensive Meta-Analysis (CMA) software. Functional analyses were carried out through LDlink, HaploReg, and RegulomeDB. The impact of each single nucleotide polymorphism on gene expression profiles and transcription factor binding sites were predicted by the RegulomeDB. 5, 6, and 1d scores were assigned to rs3746444, rs1062577, and rs1049174 by this scoring system, respectively. RegulomeDB scores of rs3746444-MYH7B/MIR499A and rs1062577-ESR1 suggested that they are not putative functional single nucleotide polymorphisms; and may not associate with significant eQTL signals. The “1d” score for rs1049174-RP11-277P12.20 confirmed an association with the expression of the target gene. Proxy variants rs6088678 and rs2617160 have been identified using LDlink in non-coding segments. They were in strong linkage disequilibrium (LD) with single nucleotide polymorphisms rs3746444 and rs1049174, respectively. Also, non-coding variants rs6088678-TRPC4AP and rs2617160- RP11-277P12.20 with high-ranked scores showed the strongest related-expression. This work provides a rapid and direct in silico-based approach for the identification of functional genetic variants in the breast cancer. These analyses were conducted to evaluate the association of intended SNPs with the regulatory elements of histones, DNases, motif changes, and selected eQTL signals. It can be extended to some other complex single nucleotide polymorphism-related diseases.

Meta-analysis of Hsa-mir-499 polymorphism (rs3746444) for cancer risk: evidence from 31 case-control studies

BackgroundMicroRNAs (miRNAs) are a family of endogenous, small and non-coding RNAs that regulate gene expression negatively at the post-transcriptional level by suppressing translation or degrading target mRNAs, and are involved in diverse biological and pathological processes. Single nucleotide polymorphisms (SNPs) which are located in the miRNA-coding genes may participate in the process of development and diseases by altering the expression of mature miRNA. Recent studies investigating the association between hsa-mir-499 polymorphism (rs3746444) and cancer risk have yielded conflicting results.MethodsIn this meta-analysis, we conducted a search of case–control studies on the associations of SNP rs3746444 with susceptibility to cancer in electronic databases. A total of 31 studies involving 12799 cases and 14507 controls were retrieved and the strength of the association was estimated by pooled odds ratios (ORs) and 95% confidence intervals (CIs). Hardy-Weinberg equilibrium (HWE) was assessed by the goodness-of-fit chi-square test in controls. Subgroup analyses were done by racial descent and cancer type. Publication bias of literatures was evaluated by visual inspection of funnel plots and the linear regression asymmetry test by Egger et al. Sensitivity analysis was conducted by excluding one study at a time to examine the influence of individual data set on the pooled ORs.ResultsOverall, significant association between rs3746444 polymorphism and susceptibility to cancer was identified in TC versus TT and TC/CC versus TT (dominant) models. In the stratified analyses, increased risks were found in Asians, but not in Caucasians in all comparison models tested. Moreover, significant association with an increased risk was found in Chinese population. Also, much higher significant association with increased cancer risks were found in Iranian population. In different cancer types, a decreased risk was found in esophageal cancer.ConclusionOur meta-analysis suggested that hsa-mir-499 rs3746444 T > C polymorphism is associated with the risk of cancer in Asians, mainly in Iranian and Chinese population. However, rs3746444 T > C polymorphism is negatively associated with the risk of esophageal cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0126-1) contains supplementary material, which is available to authorized users.

Noncoding RNA–related polymorphisms in pediatric acute lymphoblastic leukemia susceptibility

Evidence for an inherited genetic risk for pediatric acute lymphoblastic leukemia has been provided in several studies. Most of them focused on coding regions. However, those regions represent only 1.5% of the entire genome. In acute lymphoblastic leukemia (ALL), it has been suggested that the expression of microRNAs (miRNAs) is dysregulated, which suggests that they may have a role in ALL risk. Changes in miRNA function may occur through single-nucleotide polymorphisms (SNPs). Therefore, the aim of this study was to evaluate whether polymorphisms in pre-miRNAs, and/or miRNA-processing genes, contribute to a predisposition for childhood ALL. In this study, we analyzed 118 SNPs in pre-miRNAs and miRNA-processing genes in 213 B-cell ALL patients and 387 controls. We found 11 SNPs significantly associated with ALL susceptibility. These included three SNPs present in miRNA genes (miR-612, miR-499, and miR-449b) and eight SNPs present in six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1, CNOT1, and CNOT6). Among the 118 SNPs analyzed, rs12803915 in mir-612 and rs3746444 in mir-499 exhibited a more significant association, with a P value <0.01. The results of this study indicate that SNP rs12803915 located in pre-mir-612, and SNP rs3746444 located in pre-mir-499, may represent novel markers of B-cell ALL susceptibility.

Two functional polymorphisms in microRNAs and lung cancer risk: a meta-analysis

MicroRNAs are involved in several biological processes including cell apoptosis and proliferation, stress resistance, and fat metabolism, and act as tumor suppressors by malignant transformation of human cells. The aim of this study was to identify the associations of single nucleotide polymorphisms (SNPs) rs11614913 and rs3746444 with lung cancer risk. In this meta-analysis with 2,219 cases and 2,232 controls for SNP rs11614913 and 1,685 cases and 1,690 controls for SNP rs3746444, we summarized five case-control studies by searching databases of PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI). Lung cancer risk associated with the two SNPs was estimated by odd ratios (ORs) with 95% confidence intervals (CIs). SNP rs11614913 (OR 0.88, 95% CI 0.78-1.00 for TT vs. CT + CC) was found to be potentially associated with a decreased risk of lung cancer. However, we found no association between SNP rs3746444 and lung cancer risk. In the subgroup analysis by ethnicity, a negative association was also observed in Asians for SNP rs11614913, but a nonsignificant association for SNP rs3746444. Our meta-analysis provides evidence for potential protective effects on lung cancer risk associated with SNP rs11614913, particularly in Asian populations. Further, larger studies are necessary to validate the findings.

Association of polymorphisms in pre-miRNA with inflammatory biomarkers in rheumatoid arthritis in the Chinese Han population

The aim of this study was to detect the association between 2 single nucleotide polymorphisms (SNPs), rs2910164 G>C and rs3746444 T>C, in pre-miRNA (hsa-mir-146a and hsa-mir-499) and the chronic inflammation in the Chinese Han population with rheumatoid arthritis (RA). Two hundred sixty-two Han Chinese patients with RA were recruited in this study. The SNPs were genotyped by polymerase chain reaction restriction fragment length polymorphism. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and the plasma concentrations of interleukin (IL)-6, tumor necrosis factor α (TNF-α), and transforming growth factor β1 (TGF-β1) were measured. There was a significant difference in the levels of CRP and ESR among different genotypes in rs3746444 (p = 0.031 and p = 0.047, respectively). The heterozygote CT had significantly higher levels of CRP and ESR compared with homozygotes CC and TT. No significant association was observed between the SNP rs2910164 and the levels of CRP, ESR, IL-6, TNF-α, and TGF-β1 (all p > 0.05). The results of this study provided the first evidence that the SNP rs3746444 in pre-miR-499 could affect the inflammatory reaction in patients with RA. The findings were significant and might contribute to the clinical assessment of inflammatory activity, which in turn may influence therapeutic decision making.

Association study of single nucleotide polymorphisms in pre-miRNA and rheumatoid arthritis in a Han Chinese population

The aim of this study was to perform an association study between two single nucleotide polymorphisms (SNPs) rs2910164 G>C and rs3746444 T>C in pre-miRNA (hsa-mir-146a and hsa-mir-499) and rheumatoid arthritis (RA) in the Han Chinese population. 208 Han Chinese patients with RA and 240 healthy controls were recruited in this study. The SNPs was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Anti-cyclic citrullinated peptide (anti-CCP) antibody was measured by enzyme linked immunosorbent assay and rheumatoid factor (RF) was measured by rate nephelometry. The genotype frequencies between cases and controls were compared by χ(2) analysis. No significant association between the SNPs (rs2910164 and rs3746444) and RA was observed (P = 0.631 and 0.775, respectively), and the SNPs did not show any association with the RF-positive (P = 0.631 and 0.775, respectively). However, there was a significant difference on the level of anti-CCP antibody between different genotypes in rs3746444 (P = 0.007). The heterozygote CT had significantly higher level of anti-CCP antibody compared with homozygote CC and TT (P = 0.054 and 0.003, respectively). We first investigated the association between the SNPs (rs2910164 G>C and rs3746444 T>C) in the pre-miRNA (hsa-mir-146a and hsa-mir-499) and RA in a Han Chinese population. We did not find a significant association between the SNPs and the susceptibility to RA, while the SNP rs3746444 may affect anti-CCP antibody production.