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    The functional polymorphisms of miR-146a are associated with susceptibility to severe sepsis in the Chinese population. Shao Yiming,Li Jia,Cai Yujie,Xie Yuliu,Ma Guoda,Li You,Chen Yanyan,Liu Gen,Zhao Bin,Cui Lili,Li Keshen Mediators of inflammation MicroRNA-146a (miR-146a) acts as a pivotal regulatory molecule in immune response and various diseases, such as carcinoma and autoimmune diseases. Growing evidences have demonstrated the association of miR-146a gene single-nucleotide polymorphisms (SNPs) with risk of several diseases, but no genetic relevance studies of miR-146a gene polymorphisms to sepsis have been reported by now. Our study has analyzed the association of sepsis with two functional miR-146a gene SNPs rs2910164 G/C and rs57095329 A/G in a Chinese Han population (226 sepsis cases; 206 healthy controls). Our results indicated a higher prevalence of the miR-146a gene SNP rs2910164 C allele and CC genotype in patients with severe sepsis (rs2910164G versus rs2910164C: P = 0.0029, odds ratio (OR) = 1.664; GG+GC versus CC: P = 0.0045, OR = 1.947). Neither the genotype nor the allele in rs57095329 showed significant differences between the septic cases and the controls (P = 0.5901 and 0.3580, resp.), and no significant difference was observed in the subgroups. In addition, we confirmed that the two SNPs rs2910164 and rs57095329 could functionally affect the miR-146a expression levels and the reduction of miR146a was accompanied with the upregulation of the expression levels of TRAF-6 and IRAK-1 in severe sepsis patients. This present study might provide valuable clinical evidence that miR-146a gene polymorphism rs2910164 is associated with the risk of severe sepsis. 10.1155/2014/916202
    Genetic variants of MicroRNA-related genes in susceptibility and prognosis of end-stage renal disease and renal allograft outcome among north Indians. Misra Maneesh K,Pandey Shashi K,Kapoor Rakesh,Sharma Raj K,Agrawal Suraksha Pharmacogenetics and genomics BACKGROUND AND AIM:MicroRNAs are important molecules of the innate and adaptive immune system, which may play an important role in maintaining normal immune homeostasis. The aim of this study was to investigate the impact of MIR146A C>G (rs2910164), MIR149 T>C (rs2292832), MIR196A2 T>C (rs11614913), and MIR499A A>G (rs3746444) single nucleotide polymorphisms (SNPs) among end-stage renal disease (ESRD) and acute allograft rejection (AR) cases. MATERIALS AND METHODS:Genotyping of MicroRNA SNPs was performed using a PCR, followed by restriction fragment length polymorphism in 350 ESRD patients and 350 age-matched, sex-matched, and ethnically matched controls. RESULTS:We observed an increased risk of almost two-fold for ESRD and three-fold for AR cases under univariate and multivariate models for mutant genotypes of rs2910164, rs11614913, and rs3746444 SNPs. Subsequently, no susceptible/protective effect was observed for rs2292832 SNP with ESRD and AR cases. Interestingly, all the SNPs that were significant after multiple comparisons in ESRD and AR cases remained significant in the bootstrap analysis, providing internal validation to our initial observations. Survival analysis showed that the mutant genotypes of rs2910164, rs11614913, and rs3746444 SNPs were associated with the lowest overall survival compared with heterozygous and wild genotypes among renal allograft recipients. The crude and adjusted hazard ratios in univariate and multivariate Cox regression models showed an almost two-fold increased risk for overall survival against mutant genotypes of rs2910164, rs11614913, and rs3746444 SNPs in renal allograft recipients. CONCLUSION:These results suggest that the variants of MicroRNA SNPs, namely, rs2910164, rs11614913, and rs3746444, might be involved in susceptibility to ESRD and AR. 10.1097/FPC.0000000000000074
    A single nucleotide polymorphism in primary-microRNA-146a reduces the expression of mature microRNA-146a in patients with Alzheimer's disease and is associated with the pathogenesis of Alzheimer's disease. Zhang Bin,Wang Aihong,Xia Cuiping,Lin Qunfeng,Chen Chunfu Molecular medicine reports Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia among the aging population. Although the incidence of the disease continues to increase, no cure has been developed. Effective treatment is restricted not only due to the lack of curative medicine, but also due to limited understanding of the underlying mechanisms and the difficulties in accurately diagnosing AD in its earliest stages prior to clinical symptoms. Micro (mi) RNAs (miR) have gained increasing attention in the investigation of neurodegenerative diseases. Previous reports have demonstrated that deregulation of miR‑146a‑5p is associated with the pathogenesis of human AD. In the present study, the coding region of primary (pri)‑miR‑146a in patients with AD was scanned and the rare C allele of rs2910164 was found to be associated with AD. Using reverse transcription quantitative polymerase chain reaction, it was demonstrated that site variation reduced the expression of mature miR‑146a‑5p. Notably, a reduction in the expression of miR‑146a‑5p led to less efficient inhibition of target genes, including Toll‑like receptor (TLR)2, which is important in the pathogenesis of AD. Biological function investigations in RAW264.7 cells indicated that, compared with the G allele, the rare C allele upregulated the expression of tumor necrosis factor‑α following stimulation with β‑amyloid. These findings suggested that one common polymorphism in pri‑miR‑146a may contribute to the genetic predisposition to AD by disrupting the production of miR‑146a‑5p and affecting the expression and function of TLR2. 10.3892/mmr.2015.3968
    Association between microRNA polymorphisms and the risk of inflammatory bowel disease. Zhu Min,Li Diangeng,Jin Meiling,Li Mingyang Molecular medicine reports Common single nucleotide polymorphisms (SNPs) in precursor microRNAs may change their properties via altering the expression of miRNAs, resulting in diverse functional consequences. The present study evaluated the effects of four common SNPs in pro-miRNAs on the risk of inflammatory bowel disease (IBD) and IBD‑associated colorectal cancer (IBD-CRC). In a hospital based case‑control investigation in a Chinese population, 468 patients with IBD and 450 age- and gender-matched healthy subjects were enrolled in the present study. The SNPs were genotyped using a polymerase chain reaction (PCR)-restriction fragment length polymorphism technique. The expression levels of the miRNAs were detected by reverse transcription‑PCR. For rs2910164, the risk of IBD was significantly increased in the GC and CC genotypes. The mean expression levels of mir‑146a in the CC and GC genotypes were lower, compared with that of the GG genotype. For rs2292832, an increased risk of IBD was detected in the recessive model of the TT genotype, compared with the combination of the CT and CC genotypes. The [T] allele was found to be at increased significantly, with a 1.268‑fold increased risk of IBD, compared with the [C] allele. The mean expression levele of mir‑149 expression level in the TT genotype was lower, compared with that of the CC genotype. For rs11614913, the risk of IBD‑CRC was significantly increased in the CC genotype, compared with the TT genotype. In the dominant model, the CC genotype had a high risk of IBD‑CRC, compared with the combination of the CT and TT genotypes. These findings suggested that mir-146a rs2910164 and mir‑149 rs2292832 may be associated with the increased risk of IBD via alterations in the expression levels of miRNAs. Therefore, mir‑196a rs11614913 may contribute to the progression of IBD-CRC. 10.3892/mmr.2016.5157
    Polymorphisms in MIR122, MIR196A2, and MIR124A Genes are Associated with Clinical Phenotypes in Inflammatory Bowel Diseases. Ciccacci Cinzia,Politi Cristina,Biancone Livia,Latini Andrea,Novelli Giuseppe,Calabrese Emma,Borgiani Paola Molecular diagnosis & therapy BACKGROUND:Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial disorders that result from a dysregulated inflammatory response to environmental factors in genetically predisposed individuals. Recently, microRNAs (miRNAs) have been shown to be involved in the development of IBDs. AIMS:We investigated common variants in five miRNA genes in a cohort of Italian IBD patients, to evaluate their possible role in the disease's susceptibility and phenotype manifestations. METHODS:The analysis included 267 CD patients, 207 UC patients, and 298 matched healthy controls. Polymorphisms in the MIR122, MIR499, MIR146A, MIR196A2, and MIR124A genes were evaluated by allelic discrimination assay. RESULTS:We did not find associations between mir polymorphisms and IBD susceptibility. In both diseases, rs17669 and rs11614913 (MIR122 and MIR196A2) seem to contribute to clinical phenotypes: ileal location in CD (odds ratio [OR] = 1.82, p = 0.03; OR = 0.51, p = 0.01), and left-sided extent in UC (OR = 0.43, p = 0.05; OR = 0.28, p = 0.002). In CD, the MIR124A polymorphism (rs531564) contributed to colon location (p = 0.03, OR = 2.74). Finally, the variant allele of rs11614913 was associated with early age at onset in both diseases (p = 0.05 and p = 0.02). CONCLUSIONS:We showed for the first time that polymorphisms in MIR122, MIR196A2, and MIR124A could play a role in clinical phenotype modulation in IBD. 10.1007/s40291-016-0240-1
    Genetic variation in microRNA genes and prostate cancer risk in North Indian population. George Ginu P,Gangwar Ruchika,Mandal Raju K,Sankhwar Satya N,Mittal Rama D Molecular biology reports Recent evidence indicates the involvement of microRNAs (miRNAs), in cell growth control, differentiation, and apoptosis, thus playing a role in tumorigenesis. Single-nucleotide polymorphisms (SNPs) located at miRNA-binding sites (miRNA-binding SNPs) are likely to affect the expression of the miRNA target and may contribute to the susceptibility of humans to common diseases. We genotyped SNPs hsa-mir196a2 (rs11614913), hsa-mir146a (rs2910164), and hsa-mir499 (rs3746444) in a case-control study including 159 prostate cancer patients and 230 matched controls. Patients with heterozygous genotype in hsa-mir196a2 and hsa-mir499, showed significant risk for developing prostate cancer (P = 0.01; OR = 1.70 and P ≤ 0.001; OR = 2.27, respectively). Similarly, the variant allele carrier was also associated with prostate cancer, (P = 0.01; OR = 1.66 and P ≤ 0.001; OR = 1.97, respectively) whereas, hsa-mir146a revealed no association in prostate cancer. None of the miRNA polymorphisms were associated with Gleason grade and bone metastasis. This is the first study on Indian population substantially presenting that individual as well as combined genotypes of miRNA-related variants may be used to predict the risk of prostate cancer and may be useful for identifying patients at high risk. 10.1007/s11033-010-0270-4
    miRNA polymorphisms and risk of premature coronary artery disease. Agiannitopoulos Konstantinos,Samara Pinelopi,Papadopoulou Miranta,Efthymiadou Astradeni,Papadopoulou Eirini,Tsaousis Georgios N,Mertzanos George,Babalis Dimitrios,Lamnissou Klea Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese OBJECTIVE:Several microRNA (miRNA) polymorphisms have been associated with susceptibility to specific health disorders, including cardiovascular diseases. The aim of the present study was to investigate whether four well-studied miRNA polymorphisms in non-Caucasian populations, namely miR146a G>C (rs2910164), miR149 C>T (rs2292832), miR196a2 C>T (rs11614913) and miR499 A>G (rs3746444), contribute to the risk for the development of premature Coronary Artery Disease (CAD) in the Greek population. METHODS:We used a case-control study to examine these associations in 400 individuals: 200 CAD patients [including a subgroup of myocardial infraction (MI) patients] and 200 healthy controls, all of Greek origin. MiRNA polymorphisms were genotyped using three different assays: Polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP), High resolution Melting (HRM) and Sanger sequencing. RESULTS:Two of these polymorphisms, miR196a2 C>T (rs11614913) and miR499 A>G (rs3746444) were found to be strongly associated with increased risk for CAD (p=0.0388 and p=0.0013, respectively) and for MI (p=0.0281 and p=0.0273, respectively). Furthermore, miR146C-miR149C-miR196T-miR499G allele combination appeared to be significantly related to CAD (p=0.0185) and MI (p=0.0337) prevalence. CONCLUSIONS:Our results suggest that at least two of the studied polymorphisms, miR196a2 C>T (rs11614913) and miR499 A>G (rs3746444), as well as the miR146C-miR149C-miR196T-miR499G allele combination could represent useful biomarkers of CAD and/or MI susceptibility in the Greek population. These special genetic characteristics, in combination with environmental factors and personal habits, might contribute to CAD and/or MI prevalence. 10.1016/j.hjc.2020.01.005
    Correlation of miR-146a-5p plasma levels and rs2910164 polymorphism with left ventricle outflow tract obstruction in hypertrophic cardiomyopathy. Ntelios Dimitrios,Efthimiadis Georgios,Zegkos Thomas,Didagelos Matthaios,Katopodi Theodora,Meditskou Soultana,Parcharidou Despoina,Karvounis Haralampos,Tzimagiorgis Georgios Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese OBJECTIVE:Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium that is characterized by phenotypic variability among patients. miR-146a is a small non-coding RNA that is well known for its role in inflammation and myocardial hypertrophy. The aim of this study is to evaluate the role of miR-146a as a candidate genetic factor influencing HCM phenotype. METHODS:In this study, 140 HCM patients and 112 control individuals were genotyped for the rs2910164 single nucleotide polymorphism (SNP) in the MIR146A gene; using this data, the correlation between different genotypes and clinical features of the disease were determined. Additionally, plasma levels of miR-146a-5p were determined in 50 HCM patients and 30 control individuals by using qPCR. RESULTS:The incidence of GC and CC genotypes were significantly lower in HCM patients (odds ratio (OR) = 0.5 [0.3-0.8], p = 0.007). The GC/CC genotypes in the dominant genetic model positively correlated with the presence of left ventricle outflow tract (LVOT) obstruction (OR = 2.3 [1.2-4.7] and p = 0.018), a higher left ventricle mass index (118 ± 47 g/m vs 92 ± 42 g/m and p = 0.02), and increased left ventricle end-diastolic diameter (4.66 ± 0.64cm vs 4.39 ± 0.7cm and p = 0.026). Atrial fibrillation was significantly higher in patients homozygous for the C allele (OR = 10.6 [2-55], p = 0.003). Interestingly, the plasma levels of miR-146a-5p were significantly increased in HCM patients with LVOT obstruction. CONCLUSION:Our findings indicate that the C allele of the rs2910164 SNP might be under negative selection in HCM patients. Additionally, plasma levels of miR-146a-5p and GC/CC genotypes are indicative of the obstructive phenotype in HCM patients. 10.1016/j.hjc.2020.04.015
    A comprehensive evaluation of single nucleotide polymorphisms associated with hepatocellular carcinoma risk in Asian populations: A systematic review and network meta-analysis. Zhang Chi,Ye Zhuomiao,Zhang Ziting,Zheng Jinghui,Tang Youming,Hou Encun,Huang Zhihan,Meng Li Gene BACKGROUND:Single nucleotide polymorphisms (SNPs) have been inconsistently associated with hepatocellular carcinoma (HCC) risk. This meta-analysis aimed to synthesize relevant data on SNPs associated with HCC in the Asian population. METHODS:Databases were searched to identify association studies of SNPs and HCC in Asians published through January 2019. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on 41 studies (13,167 patients with HCC and 15,886 noncancer controls). Network meta-analysis and Thakkinstian's algorithm were used to select the most appropriate genetic model, along with false positive report probability (FPRP) for noteworthy associations. RESULTS:Eleven SNPs meeting the inclusion criteria were tested for association with HCC, including CCND1 rs9344, PTGS2 rs689466, IL18 rs187238 and rs1946518, KIF1B rs17401966, MDM2 rs2279744, MIR146A rs2910164, MIR149 rs2292832, MIR196A2 rs11614913, MIR499A rs3746444, and TGFB1 rs1800469. A significant increase for HCC risk was observed for MDM2 rs2279744, and the dominant (pooled OR = 1.59, 95% CI: 1.26-2.00) and codominant (pooled OR = 1.37, 95% CI: 1.18-1.60) models were determined to be the most appropriate models. MIR499A rs3746444 also showed a significant association with HCC risk under the allele contrast model (pooled OR = 1.36, 95% CI: 1.05-1.77). Only the significance of MDM2 rs2279744 was noteworthy (FPRP < 0.2). CONCLUSIONS:MDM2 rs2279744 is associated with HCC susceptibility in Asians, and the dominant and codominant models are likely the most appropriate models to estimate HCC risk. 10.1016/j.gene.2020.144365
    The single nucleotide variant n.60G>C in the microRNA-146a associated with susceptibility to drug-resistant epilepsy. Boschiero Matheus Negri,Camporeze Bruno,Santos Jéssica Silva Dos,Costa Leandro Borsari da,Bonafé Gabriel Alves,Queiroz Luciano de Souza,Van Roost Dirk,Marson Fernando Augusto Lima,de Aguiar Paulo Henrique Pires,Ortega Manoela Marques Epilepsy research OBJECTIVE:The aim of this study was to evaluate single nucleotide variants (SNVs) n.-411A > G (rs57095329) and n.60 G > C (rs2910164) in microRNA (miR)-146a, related to suppressing of TRAF6 with risk for epilepsy, as well as miR-146a and TRAF6 levels. METHODS:DNAs were extracted from epileptogenic tissues and blood leukocytes from drug-resistant epilepsy patients and healthy-individuals, respectively. Genotypes were identified by real-time PCR. Hardy-Weinberg equilibrium (HWE) and Fisher or X tests evaluated the difference between groups. The disease risk was assessed by odds ratio (OR) with 95 % confidence interval (95 %CI). The prognostic impact on probability seizure-free survival (PSF) was evaluated by Kaplan-Meier and log-rank tests. RESULTS:For rs57095329 both control and patient samples were not in HWE (p < 0.05) and the genotypes prevalence was similar in patients and controls (p>0.05). For rs2910164, control samples were in HWE (p = 0.61), contrasting with patients (p = 0.03), and similar frequencies of wild-type homozygous (GG) (43.4 % vs. 34.4 %, p = 0.2) and variant (CC) genotypes (8.0 % vs. 6.6 %, p = 0.6) were observed in patients and controls, respectively. However, increased frequency of heterozygous (GC) was observed in patients compared to controls (59.0 % vs. 42.7 %, p = 0.04) with 1.98 (95 %CI=1.09-3.57) risk for epilepsy. The miR-146a expression level in the epileptogenic tissues was lower in the GC (p = 0.02) and CC (p = 0.09) compared to GG genotype. TRAF6 expression level was higher in CC than in GG genotype (p = 0.09). Interestingly, there was an increased frequency of patients harboring GC genotype and less time until surgery compared to patients harboring GG or CC (36.06 % vs. 11.5 %, p = 0.01), confirmed by PSF (p = 0.04). CONCLUSIONS:The GC genotype for SNV rs2910164 appears associated with susceptibility to drug-resistant epilepsy due to the decreased MIR146a expression, favoring NF-kB pathway through TRAF6. 10.1016/j.eplepsyres.2020.106305
    An association study between MiR-146a and INSR gene polymorphisms and hypertensive disorders of pregnancy in Northeastern Han Chinese population. Lu Rui,Liu Nana,Feng Xiu,Feng Yanan,Zhang Shuang,Wu Yingnan,Jia Tianshuang,Yang Xuan,Lee Leo Tsz On,Sun Litao Placenta INTRODUCTION:Hypertensive disorders of pregnancy(HDP) is a complex and challenging group of pregnancy complications that is one of the leading causes of maternal and fetal death worldwide. Recent studies have shown that the single nucleotide polymorphism(SNP) may play a role in the pathogenesis of HDP. This study aimed to investigate the association of MiR-146a rs2910164 and insulin receptor(INSR) rs2059806 SNPs with HDP and their associated complications in the Han population of Northeast China. METHODS:A total of 240 HDP patients and 380 healthy controls were selected for genotype determination. For the most special and high incidence of HDP, we also studied the SNPs in association with pre-eclampsia(PE) patients. In addition, HDP complicated with gestational diabetes mellitus(GDM) patients was further analyzed to identify the association between SNPs and HDP-related complications. Multivariate logical regression analysis combined with 10, 000 permutation test corrections was used to analyze the association of MiR-146a and INSR SNPs with HDP. RESULTS:After adjusting for relevant factors, MiR-146a rs2910164 or INSR rs2059806 SNPs were not significantly different between HDP or PE patients and healthy controls(P>0.05). Meanwhile, MiR146a rs2910164 and INSR rs2059806 SNPs were not significantly different between HDP complicated with GDM and control group. DISCUSSION:Our data indicates that MiR-146a rs2910164 and INSR rs2059806 SNPs may not be significantly related with HDP in the Han population of Northeast China living in Heilongjiang Province. 10.1016/j.placenta.2020.11.011
    Associations of Single Nucleotide Polymorphism in miR-146a Gene with Susceptibility to Breast Cancer in the Iranian Female. Siasi Elham,Solimani Mahkameh Asian Pacific journal of cancer prevention : APJCP BACKGROUND:MicroRNAs (miRNAs), short regulatory RNAs, function as negative regulators able to modulate gene expression. Just as other genetic variant, single nucleotide polymorphisms (SNPs) in miRNA genes, may have an impact on their expression and/or maturation and hence leading to different consequences in carcinogenesis. Accordingly, this study aimed to assess the frequency of miR-146a G/C (rs2910164) polymorphism and its association with susceptibility to breast cancer in Iranian women. METHODS:We conducted a case-control study using Tetra ARMS polymerase chain reaction (Tetra ARMS PCR) method in 100 Iranian female participants (50 breast cancer patients and 50 controls). Besides, a number of sequenced samples were chosen to confirm the accuracy of genotyping by Tetra ARMA PCR. SPSS software was utilized for all statistical analyses. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were applied to analyze the association between the SNP frequency and breast cancer. RESULTS:The frequency of genotypes for G/G, G/C, and C/C were 23 (46%), 26 (52%), and 1 (2%) among cases and 15 (30%), 33 (66%), and 2(4%) among controls, respectively. The results generated by the groups did not show any significant correlation between miR-146a G/C (rs2910164) polymorphism and breast cancer, either at genotype or allele levels (P>0.05). F-SNP-based in silico analysis indicated possible modifications in transcriptional regulations induced by miR-146a G/C (rs2910164) variations. CONCLUSION:Overall, our results indicated no correlation between miR-146a G/C (rs2910164) polymorphism and genetic susceptibility to breast cancer in Iranian female populations. However, these findings need to be further confirmed by analyses of a larger number of cases. 10.31557/APJCP.2020.21.6.1585
    A genetic variant in microRNA-146a is associated with sporadic breast cancer in a Southern Brazilian Population. Brincas Heloisa Magagnin,Augusto Danillo G,Mathias Carolina,Cavalli Iglenir João,Lima Rubens Silveira de,Kuroda Flávia,Urban Cícero de Andrade,Gradia Daniela Fiori,de Oliveira Jaqueline,de Almeida Rodrigo Coutinho,Ribeiro Enilze Maria de Souza Fonseca Genetics and molecular biology MicroRNAs (miRNAs) play an essential role in gene expression and affect the development of tumours, including breast cancer (BC). Polymorphisms in miRNA genes can affect the interaction of miRNAs with their target messenger RNA by interfering, creating or disrupting target sites. The single nucleotide polymorphism (SNP) rs2910164, located in the seed region of miR146a, was shown to be associated with BC among different populations. In the present study, we investigated whether rs2910164 is associated with BC in 326 patients and 411 controls from a Brazilian population of predominantly European ancestry. The presence of the allele rs2910164*C was associated with an increased risk of BC (OR=1.4, 95% CI=1.03-1.85, p = 0.03). We also analysed publicly available RNA-seq data to evaluate if miR146a is differentially expressed in different subtypes of BC. Genotyping was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP). By leveraging public data from TCGA database, we analysed 461 patients and found that miR146a is significantly more expressed in BC than in non-tumor tissue (1.47 fold, p = 0.02) and is expressed to a greater degree in aggressive BC subtypes. 10.1590/1678-4685-GMB-2019-0278
    A single nucleotide polymorphism in hsa‑miR‑146a is responsible for the development of bronchial hyperresponsiveness in response to intubation during general anesthesia. Luan Yong,Li Dongjiang,Gao Lulu,Xie Sha,Pei Ling Molecular medicine reports Bronchial hyperresponsiveness (BHR) is the most common clinical manifestation identified in asthmatic patients, and intubation is the major factor that stimulates the airway of patients receiving general anesthetic. In the present study, nitric oxide synthase 1 (NOS1) was identified as a target gene of micro (mi)R‑146a using in silico analysis and luciferase assay. Furthermore, the regulatory role of miR‑146a was demonstrated by the observation that the NOS1 expression level in pulmonary artery smooth muscle cells (PASMCs) transfected with miR‑146a mimics was significantly downregulated and the NOS1 expression level in PASMCs transfected with miR‑146a inhibitors was significantly upregulated. Additionally, it was identified that a polymorphism in pri‑miR‑146 interfered with mature processing and reduced the quantity of mature miRNA. To assess the association between the polymorphism and the development of BHR, 563 patients with basic pulmonary diseases, such as asthma, emphysema or bronchitis were enrolled in the present study. Each participant received a general anesthetic and the development of BHR was evaluated. The miR‑146a rs2910164 polymorphism CC genotype was identified to be significantly associated with a decreased risk of BHR in response to intubation when compared with the GG or GC genotype (odds ratio, 0.38; confidence interval, 0.18‑0.78). These findings indicate that the miR‑146a rs2910164 polymorphism is associated with a decrease risk of BHR, and the CC genotype increased the level of NOS1 expression, which was physiologically inhibited by wild‑type miR‑146a. 10.3892/mmr.2016.5499
    The rs2910164:G>C SNP in the MIR146A gene is not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Garcia Amandine I,Cox David G,Barjhoux Laure,Verny-Pierre Carole,Barnes Daniel, ,Antoniou Antonis C,Stoppa-Lyonnet Dominique,Sinilnikova Olga M,Mazoyer Sylvie Human mutation The rs2910164:G>C SNP is located in the gene for miR-146a, a microRNA that binds the 3' UTR of the BRCA1 transcript. Preliminary data based on the analysis of a small number of cases suggested that this single nucleotide polymorphism (SNP) might be associated with the age of onset of familial breast and ovarian cancer. This effect was not confirmed on a large series of familial breast cancer cases negative for a BRCA1 or BRCA2 mutation. We show here a lack of association of the rs2910164:G>C SNP with breast cancer risk in a series of 1,166 BRCA1 and 560 BRCA2 mutation carriers. In conclusion, the polymorphism in the miR-146a gene is unlikely to be of substantial significance regarding breast cancer risk. 10.1002/humu.21539
    Rs2910164 in microRNA‑146a confers an elevated risk of depression in patients with coronary artery disease by modulating the expression of NOS1. Zhang Xinling,Huo Qianqian,Sun Wei,Zhang Chunxiang,Wu Zongyin,Xing Bing,Li Qiang Molecular medicine reports Depression has been well established as an independent predictor of mortality and cardiac morbidity rates in patients with coronary artery disease (CAD). Evidence has shown that single nucleotide polymorphisms located in pre‑microRNA (miRNA) or mature miRNA may modify various biological processes and affect the process of carcinogenesis, and the downregulation of neuronal nitric oxide synthase 1 (NOS1) can induce depression. It has been shown that NOS1 is the target gene of miR‑146a, and that the rs2910164 G/C polymorphism can downregulate the expression of miR‑146a. In the present study, computational analysis was used to identify the target of miR‑146a, and a luciferase reporter assay system was used to validate NOS1 as a target gene of miR‑146a. In addition, U251 cells were treated with miR‑146a mimics/inhibitors to verify the negative regulatory association between miR‑146a and NOS1. Reverse transcription‑quantitative polymerase chain reaction analysis and western blot analysis were used to estimate the mRNA expression of NOS1 and the expression of miR‑146a. The results showed that the 'seed sequence' was located within the 3'‑untranslated region of NOS1 by searching an online miRNA database (www.mirdb.org), and the luciferase reporter assay confirmed that NOS1 was a direct target gene of miR‑146a. It was also found that the mRNA and protein expression levels of NOS1 in U251 cells treated with miR‑146a mimics and NOS1 small interfering RNA were substantially downregulated, compared with cells treated with the scramble control. The cells treated with miR‑146a inhibitors showed increased expression of NOS1. In addition, the presence of a minor allele of the rs2910164 polymorphism was significantly associated with risk of depression in patients with CAD. Taken together, the findings indicated a decreased risk of depression in the patients with CAD who were carriers of the miR‑146a rs2910164 C allele, and this association may be attributed to its ability to compromise the expression of miR‑146a, and thereby increase the expression of its target gene, NOS1. 10.3892/mmr.2018.8929
    MiR146a and MiR499 gene polymorphisms in Iranian periodontitis and peri-implantitis patients. Kadkhodazadeh Mahdi,Jafari Ali Reza,Amid Reza,Ebadian Ahmad Reza,Alipour Marjan Mohammad,Mollaverdi Fatemeh,Lafzi Ardeshir Journal of long-term effects of medical implants AIM:MicroRNAs (MiRs) are small noncoding RNAs that are involved in protein translation, osteoclastogenesis, and immunoregulation. Peri-implantitis and chronic periodontitis are multifactorial diseases. They are the consequence of complex interactions among host response, genetics, and environment. In the present study, we aimed to investigate the possible association between MiR146a/MiR499 gene polymorphisms and periodontitis/peri-implantitis as a first report in oral implantology. METHODS:From 197 individuals referred to Periodontology Department of Shahid Beheshti Dental School, three groups were enrolled in the assessment: 75 patients in the chronic periodontitis (CP) group, 38 patients in the peri-implantitis (PI) group, and 84 healthy subjects. DNA was extracted from fresh blood samples from the arm veins of participants and transferred to KBiosience Institute (Hoddesdon, United Kingdom) for genotyping. Chi-squared and Kruskal-Wallis tests were performed using SPSS software v.19 for statistical analyses. P-value < 0.05 was considered significant. RESULTS:The genotype frequencies in MiR 146a and MiR 499 were significantly different among the three groups. CONCLUSIONS:MiR146a (rs2910146) and MiR499 (rs3746444) gene polymorphisms may be genetic determinants for increased risk of chronic periodontitis and peri-implantitis in Iranians. More studies with larger sample sizes in different populations are necessary for determining the effect of these SNPs. 10.1615/jlongtermeffmedimplants.2013007073
    Functional polymorphisms in and are associated with systemic lupus erythematosus but not with rheumatoid arthritis or Graves' disease in Mexican patients. Alemán-Ávila Isidro,Jiménez-Morales Mayra,Beltrán-Ramírez Olga,Barbosa-Cobos Rosa Elda,Jiménez-Morales Silvia,Sánchez-Muñoz Fausto,Valencia-Pacheco Guillermo,Amezcua-Guerra Luis M,Juárez-Vicuña Yaneli,Razo-Blanco Hernández Dulce Milagro,Aguilera-Cartas María Concepción,López-Villanueva Ricardo F,Peralta-Zaragoza Oscar,Tovilla-Zárate Carlos,Ramírez-Bello Julian Oncotarget Recently, different microRNA (miRNA) gene polymorphisms have been evaluated in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves' disease (GD). In the present study, we examined three single-nucleotide polymorphisms (SNPs) located in the (rs2910164G/C), (rs11614913C/T), and (rs3746444A/G) genes. Our study population included 900 Mexican patients with RA, SLE, or GD, as well as 486 healthy control individuals with no family history of inflammatory or autoimmune diseases. Genotyping was performed using TaqMan probes and a 5' exonuclease assay. None of the investigated SNPs were associated with RA or GD susceptibility under any genetic model (co-dominant, recessive, or dominant). Genotype and allele frequencies of the rs11614913C/T polymorphism were similar between SLE cases and controls. In contrast, the rs2910164G/C and rs3746444A/G polymorphisms were associated with SLE susceptibility. These SNPs were not associated with lupus nephritis (LN). Our results suggest that polymorphisms in , and are not associated with RA or GD susceptibility. This is the first report documenting that the rs2910164G/C and rs3746444 polymorphisms are associated with SLE susceptibility but not with LN. 10.18632/oncotarget.19621
    Common MIR146A Polymorphisms in Chinese Ankylosing Spondylitis Subjects and Controls. Niu Zhenmin,Wang Jiucun,Zou Hejian,Yang Chengde,Huang Wei,Jin Li PloS one Common polymorphisms of microRNA gene MIR146A were reported as associated with different autoimmune diseases, include systemic lupus erythematosus, psoriatic arthritis, asthma and ankylosing spondylitis. In this study we investigated MIR146A SNPs in Chinese people with ankylosing spondylitis. Three common SNPs: rs2910164, rs2431697 and rs57095329 were selected and genotyped in 611 patients and 617 controls. We found no association between these SNPs and ankylosing spondylitis in our samples. 10.1371/journal.pone.0137770
    RNASEL and MIR146A SNP-SNP interaction as a susceptibility factor for non-melanoma skin cancer. Farzan Shohreh F,Karagas Margaret R,Christensen Brock C,Li Zhongze,Kuriger Jacquelyn K,Nelson Heather H, PloS one Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators, MIR146A and RNASEL, and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of MIR146A SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets (RNASEL, rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the RNASEL or MIR146A variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and MIR146A in women (ORGC = 0.73, [95%CI = 0.52-1.03]; ORCC = 0.29, [95% CI = 0.14-0.61], p-trend<0.001), and a reduction in risk, albeit not statistically significant, associated with RNASEL and SCC in men (ORAG = 0.88, [95%CI = 0.65-1.19]; ORAA = 0.68, [95%CI = 0.43-1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (ORSCC = 0.56, [95%CI = 0.38-0.81], p-interaction = 0.012) and BCC (ORBCC = 0.57, [95%CI = 0.40-0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a and may be important in NMSC etiology. 10.1371/journal.pone.0093602
    Association of the microRNA-Single Nucleotide Polymorphism rs2910164 in miR146a with sporadic breast cancer susceptibility: A case control study. Upadhyaya Akanksha,Smith Robert A,Chacon-Cortes Diego,Revêchon Gwladys,Bellis Claire,Lea Rod A,Haupt Larisa M,Chambers Suzanne K,Youl Philippa H,Griffiths Lyn R Gene BACKGROUND:Breast cancer (BC) is primarily considered a genetic disorder with a complex interplay of factors including age, gender, ethnicity, family history, personal history and lifestyle with associated hormonal and non-hormonal risk factors. The SNP rs2910164 in miR146a (a G to C polymorphism) was previously associated with increased risk of BC in cases with at least a single copy of the C allele in breast cancer, though results in other cancers and populations have shown significant variation. METHODS:In this study, we examined this SNP in an Australian sporadic breast cancer population of 160 cases and matched controls, with a replicate population of 403 breast cancer cases using High Resolution Melting. RESULTS:Our analysis indicated that the rs2910164 polymorphism is associated with breast cancer risk in both primary and replicate populations (p=0.03 and 0.0013, respectively). In contrast to the results of familial breast cancer studies, however, we found that the presence of the G allele of rs2910164 is associated with increased cancer risk, with an OR of 1.77 (95% CI 1.40-2.23). CONCLUSIONS:The microRNA miR146a has a potential role in the development of breast cancer and the effects of its SNPs require further inquiry to determine the nature of their influence on breast tissue and cancer. 10.1016/j.gene.2015.10.019
    Analysis of 75 Candidate SNPs Associated With Acute Rejection in Kidney Transplant Recipients: Validation of rs2910164 in MicroRNA MIR146A. Oetting William S,Schladt David P,Dorr Casey R,Wu Baolin,Guan Weihua,Remmel Rory P,Iklé David,Mannon Roslyn B,Matas Arthur J,Israni Ajay K,Jacobson Pamala A, Transplantation BACKGROUND:Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR. However, there are additional publications reporting a lack of this association when a different cohort of recipients is analyzed for the same single-nucleotide polymorphism. METHODS:In this report, we attempted to validate 75 common genetic variants, which have been previously reported to be associated with AR, using a large kidney allograft recipient cohort of 2390 European Americans and 482 African Americans. RESULTS:Of those variants tested, only 1 variant, rs2910164, which alters the expression of the microRNA MIR146A, was found to exhibit a significant association within the African American cohort. Suggestive variants were found in the genes CTLA and TLR4. CONCLUSIONS:Our results show that most variants previously reported to be associated with AR were not validated in our cohort. This shows the importance of validation when reporting the associations with complex clinical outcomes such as AR. Additional work will need to be done to understand the role of MIR146A in the risk of AR in kidney allograft recipients. 10.1097/TP.0000000000002659
    Common polymorphisms in MIR146a, MIR128a and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes. Ciccacci Cinzia,Morganti Roberto,Di Fusco Davide,D'Amato Cinzia,Cacciotti Laura,Greco Carla,Rufini Sara,Novelli Giuseppe,Sangiuolo Federica,Marfia Girolama A,Borgiani Paola,Spallone Vincenza Acta diabetologica Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) are common type 2 diabetes complications with a large inter-individual variability in terms of clinical manifestations and severity. Our aim was to evaluate a possible involvement of genetic polymorphisms in miRNA regions in the susceptibility to DPN and CAN. Nine polymorphisms in miRNA genes were studied in a sample of 132 type 2 diabetes patients (T2D) analysed for DPN and 128 T2D patients analysed for CAN. A genotype-phenotype correlation analysis was performed. The T allele of rs11888095 single nucleotide polymorphism (SNP) in MIR128a was significantly associated with a higher risk (ORadj = 4.89, P adj = 0.02), whereas the C allele of rs2910164 SNP in MIR146a was associated with a lower risk to develop DPN (ORadj = 0.49, P adj = 0.09), respectively. A multivariate logistic regression analysis confirmed that both SNPs contribute to DPN (p < 0.001 and p = 0.01 for MIR128a and MIR146a, respectively). MIR128a SNP significantly contributed also to DPN score (p = 0.026). Rs895819 SNP in MIR27a was significantly associated with a higher risk to develop early CAN (P adj = 0.023 and ORadj = 3.43). The rs2910164 SNP in MIR146a showed a protective effect respect to early CAN (P adj = 0.052, ORadj = 0.32) and to confirmed CAN (P adj = 0.041, ORadj = 0.13). The same SNP resulted significantly associated with a lower CAN score and a higher E/I (p = 0.002 and p = 0.003, respectively). In conclusion, we described associations of MIR128a and MIR146a SNPs with DPN susceptibility and of MIR146a and MIR27a SNPs with CAN susceptibility. This is the first study showing that genetic variability in miRNA genes could be involved in diabetic neuropathies susceptibility. 10.1007/s00592-014-0582-2
    The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of and . Strafella Claudia,Errichiello Valeria,Caputo Valerio,Aloe Gianluca,Ricci Federico,Cusumano Andrea,Novelli Giuseppe,Giardina Emiliano,Cascella Raffaella International journal of molecular sciences The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of , , , , , , , and were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (, G/A) and rs2910164 (, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications. 10.3390/ijms20071578
    Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis. Ciccacci C,Conigliaro P,Perricone C,Rufini S,Triggianese P,Politi C,Novelli G,Perricone R,Borgiani P Clinical and experimental immunology Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in chronic inflammation of the synovium and consequent cartilage and bone erosion. RA is associated strongly with the presence of rheumatoid factor (RF), and consists of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and -negative patients. This study was designed to evaluate whether relevant single nucleotide polymorphisms (SNPs) associated with RA and other autoimmune disorders are related to RF, ACPA and clinical phenotype in a cohort of biologic drugs naive Italian RA patients; 192 RA patients and 278 age-matched healthy controls were included. Clinical and laboratory data were registered. We analysed a total of 12 single nucleotide polymorphisms (SNPs) in signal transducer and activator of transcription-4 (STAT-4), interleukin (IL)-10, psoriasis susceptibility 1 candidate 1 (PSORS1C1), protein tyrosine phosphatase, non-receptor type 2 (PTPN2), endoplasmic reticulum aminopeptidase 1 (ERAP1), tumour necrosis factor receptor-associated 3 interacting protein 2 (TRAF3IP2) and microRNA 146a (MIR146A) genes by allelic discrimination assays. Case-control association studies and genotype/phenotype correlation analyses were performed. A higher risk to develop RA was observed for rs7574865 in the STAT-4 gene, while the rs1800872 in the IL-10 gene showed a protective effect. The presence of RF was associated significantly with rs1800872 variant in IL-10, while rs2910164 in MIR146A was protective. ACPA were associated significantly with rs7574865 in STAT-4. The SNP rs2233945 in the PSORS1C1 gene was protective regarding the presence of bone erosions, while rs2542151 in PTPN2 gene was associated with joint damage. Our results confirm that polymorphisms in STAT-4 and IL-10 genes confer susceptibility to RA. For the first time, we described that SNPs in PSORS1C1, PTPN2 and MIR146A genes were associated differently with a severe disease phenotype in terms of autoantibody status and radiographic damage in an Italian RA population. 10.1111/cei.12831
    Association of MIR146A rs2910164 variation with a predisposition to sporadic breast cancer in a Pakistani cohort. Ahmad Mushtaq,Ahmad Sadia,Rahman Bashir,Haq Taqweem Ul,Jalil Fazal,Shah Aftab Ali Annals of human genetics Single-nucleotide polymorphisms (SNPs) in genes coding for microRNAs (miRNAs) play a pivotal role in the progression of breast cancer (BC). We investigated the association of miR-146a rs2910164 GC polymorphism with the risk of BC in the Pakistani population. The miR-146a rs2910164 polymorphism was genotyped in 300 BC cases and 300 age- and gender-matched healthy controls using T-ARMS-PCR. Genotype and allele frequencies were calculated and the association between genotypes and the risk of BC was calculated by odds ratio (OR) and confidence interval (95%). A significant difference in genotypic frequencies (χ  = 63.10; P = <0.0001) and allelic frequencies (OR = 0.3955 (0.3132-0.4993); P = < 0.0001) was observed between cases and controls. Furthermore, we also found that miR-146 rs2910164 CC homozygote increased the risk of BC in the dominant (OR = 0.2397 (0.1629-0.3526); P = 0.0001; GG vs. GC + CC) and recessive (OR = 2.803 (1.865-4.213); P = <0.0001; CC vs. GC + GG) inheritance models. In summary, miR-146a rs2910164 GC is significantly associated with BC in the Pakistani population. To our knowledge, this is the first study that assessed MIR146a rs2910164 G > C SNP in Pakistani population. By analyzing the secondary structure of MIR146A variant, a significant structural modification was noted. Study with a larger sample size is needed to further confirm of these findings. 10.1111/ahg.12316