The role of matrix metalloproteinase-2 and miR-196a2 in bronchial asthma pathogenesis and diagnosis.

Background: Bronchial asthma is a persistent inflammatory respiratory condition that restricts the passage of air and causes hyperresponsiveness. Chronic asthma can be classified into three categories: mild, moderate, and severe. Remodeling took place as the extracellular matrix accumulated in the walls of the airways. Inflammation occurs as a result of the damage caused by matrix metalloproteinase-2 (MMP-2) to basement membrane type IV collagen. The severity of asthma may be associated with miR-196a2. The objective of our study was to investigate the underlying mechanisms and clinical relevance of miR-196a2 and MMP-2 serum levels in relation to the severity of asthma. Methods: This study recruited 85 controls and 95 asthmatics classified as mild, moderate, or severe. Expression of miR-196a2 was measured by quantitative reverse transcriptase PCR. Using the enzyme-linked immunosorbent assay (ELISA), MMP-2, IL-6, and total immunoglobulin E (IgE) levels in the serum of asthmatics of various grades were compared to a control group. MMP-2's diagnostic and prognostic potential was determined using ROC curve analysis. This study also measured blood Eosinophils and PFTs. We examined MMP-2's connections with IgE, blood Eosinophils, and PFTs. Results: The current investigation found that miR-196a2 expression was significantly higher in the control group than in asthmatic patients as a whole. The study found that severe asthmatics had higher MMP-2, IL-6, and IgE serum levels than healthy controls. We identified the MMP-2 serum concentration cutoff with great sensitivity and specificity. Significant relationships between MMP-2 serum level and miR-196a2 expression in the patient group with severe asthmatics were found. The MMP-2, IL-6, and IgE serum levels were considerably higher in mild, moderate, and severe asthmatics than controls. The miR-196a2 expression and MMP-2 serum concentration correlated positively with IgE and blood eosinophils % and negatively with all lung function tests in the asthmatic patient group.Conclusion: the study revealed that the elevated miR-196a2 expression and serum concentration of MMP-2, IL-6, and IgE associated with elevated blood eosinophils % is associated with pathophysiology and degree of asthma severity. The miR-196a2 expression and MMP-2 serum concentration have a promising diagnostic and prognostic ability in bronchial asthma.

Impact of Mir196a-2 Genotypes on Colorectal Cancer Risk in Taiwan.

We aimed to investigate the association between genotypes for mir146a and mir196a-2 and the risk of developing colorectal cancer (CRC). We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the mir146a rs2910164 and mir196a-2 rs11614913 genotypes in 362 CRC patients and 362 controls. We also assessed the interactions between these genotypes and age, gender, smoking, alcohol consumption, and BMI status on CRC risk. Additionally, the serum expression level of mir196a-2 was quantified using quantitative reverse transcription-PCR. Our findings demonstrated that among the controls, the proportions of TT, CT, and CC genotypes of mir196a-2 rs11614913 were 32.3%, 48.1%, and 19.6%, respectively. As for the cases, the proportions were 24.6%, 45.0%, and 30.4%, respectively. Logistic regression analysis revealed that the CC genotype carriers had a 2.04-fold increased risk (95% confidence interval [CI] = 1.36-3.06, p = 0.0008). Furthermore, carriers of the CT + CC genotypes also exhibited a significant association with CRC risk (odds ratio [OR] = 1.46, 95% CI = 1.06-2.03, p = 0.0261). Moreover, carriers of the CC genotype had significantly higher serum levels of mir196a-2 compared to those with the TT genotype (p < 0.0001), indicating a genotype-phenotype correlation. No association was found regarding mir146a rs2910164. In conclusion, mir196a-2 rs2910164 genotypes, along with their associated expression, can serve as predictive markers for CRC risk.

Association of miR-196a2 and miR-27a polymorphisms with gestational diabetes mellitus susceptibility in a Chinese population.

Introduction: MiR-196a2 and miR-27a play a key role in the regulation of the insulin signaling pathway. Previous studies have indicated that miR-27a rs895819 and miR-196a2 rs11614913 have a strong association with type 2 diabetes (T2DM), but very few studies have investigated their role in gestational diabetes mellitus (GDM). Methods: A total of 500 GDM patients and 502 control subjects were enrolled in this study. Using the SNPscan™ genotyping assay, rs11614913 and rs895819 were genotyped. In the data treatment process, the independent sample t test, logistic regression and chi-square test were used to evaluate the differences in genotype, allele, and haplotype distributions and their associations with GDM risk. One-way ANOVA was conducted to determine the differences in genotype and blood glucose level. Results: There were obvious differences in prepregnancy body mass index (pre-BMI), age, systolic blood pressure (SBP), diastolic blood pressure (DBP) and parity between GDM and healthy subjects (P < 0.05). After adjusting for the above factors, the miR-27a rs895819 C allele was still associated with an increased risk of GDM (C vs. T: OR=1.245; 95% CI: 1.011-1.533; P = 0.039) and the TT-CC genotype of rs11614913-rs895819 was related to an increased GDM risk (OR=3.989; 95% CI: 1.309-12.16; P = 0.015). In addition, the haplotype T-C had a positive interaction with GDM (OR=1.376; 95% CI: 1.075-1.790; P=0.018), especially in the 18.5 ≤ pre-BMI < 24 group (OR=1.403; 95% CI: 1.026-1.921; P=0.034). Moreover, the blood glucose level of the rs895819 CC genotype was significantly higher than that of the TT and TC genotypes (P < 0.05). The TT-CC genotype of rs11614913-rs895819 showed that the blood glucose level was significantly higher than that of the other genotypes. Discussion: Our findings suggest that miR-27a rs895819 is associated with increased GDM susceptibility and higher blood glucose levels.

Functional Variants in MicroRNAs (rs895819, rs11614913 and rs2910164) Are Associated with Susceptibility and Clinicopathological Features in Mexican Patients with Colorectal Cancer.

BACKGROUND: miRNAs are non-coding RNAs participating actively in the post-translational regulation of oncogenes, tumor suppressor, and DNA repair genes implicated in colorectal cancer (CRC). This study aims to examine the association of the variants miR-27a (rs895819 A>G), miR-196a2 (rs11614913 T>G) and miR-146a (rs2910164 C>G) in Mexican CRC patients. METHODS: DNA samples from 183 patients and 186 healthy Mexican subjects were analyzed. Variants were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. Association was calculated by the odds ratio (OR) and adjusted by the Bonferroni test. RESULTS: Patients carrying the G/G genotype of the rs895819 variant in the miR-27a gene showed an increased risk of CRC (19% vs 12%, P=0.013). A similar tendency was noticed for patients younger than 50 years carrying A/G (48% vs 41%, P=0.014). The A/G genotype in TNM stages I+II (55.7% vs 40.8%, P=0.011) and tumor location in the colon (69.5 vs 40.8%, P=0.001) were also increased. For the variant rs11614913 of the miR-196a2 gene, carriers of the C/C genotype showed an increased risk of CRC (32% vs 22%, P=0.009). This genotype was more frequent in TNM stage III+IV (36.8% vs 22.5%, P=0.007) and the tumor had a more recurrent location in the rectum (31.6% vs 22.5%, P=0.013). The rs2910164 variant of the miR-146a gene was found to have no significant risk associations. CONCLUSION: Our results reveal that the rs895819 variant in miR-27a and rs11614913 in miR-196a2 have a substantial impact on the development of CRC.

Effect of miR-196a2 rs11614913 Polymorphism on Cancer Susceptibility: Evidence From an Updated Meta-Analysis.

Background:MiR-196a2 rs11614913 polymorphism has been studied in a wide range of cancers throughout the years. Despite a large number of epidemiological studies performed in almost all ethnic populations, the contribution of this polymorphism to cancer risk is still inconclusive. Therefore, this updated meta-analysis was performed to estimate a meticulous correlation between miR-196a2 rs11614913 variant and cancer susceptibility. Methods: A systematic study search was carried out using PubMed, ScienceDirect, CNKI, EMBASE, Scopus, and Google Scholar databases following PRISMA guidelines to find necessary literature up to December 15, 2021. Pooled odds ratios with corresponding 95% confidence intervals were estimated using RevMan 5.4 based on ethnicities, cancer types, control sources, and genotyping methods. Results: A total of 152 studies, including 120 135 subjects (53 818 patients and 66 317 controls; 140 studies, after removing studies that deviated from HWE: 51 459 cases and 62 588 controls), were included in this meta-analysis. Quantitative synthesis suggests that the miR-196a2 rs11614913 genetic variant is significantly correlated with the reduced risk of overall cancer in CDM2, CDM3, RM, and AM (odds ratio < 1 and P < .05). It is also observed from ethnicity-based subgroup analysis that rs11614913 polymorphism is significantly (P < .05) linked with cancer in the Asian (in CDM2, CDM3, RM, AM) and the African population (in CDM1, CDM3, ODM). Stratified analysis based on the cancer types demonstrated a significantly decreased correlation for breast, hepatocellular, lung, and gynecological cancer and an increased association for oral and renal cell cancer. Again, the control population-based subgroup analysis reported a strongly reduced correlation for HB population in CDM2, RM, and AM. A substantially decreased risk was also observed for other genotyping methods in multiple genetic models. Conclusions:MiR-196a2 rs11614913 variant is significantly correlated with overall cancer susceptibility. Besides, rs11614913 is correlated with cancer in Asians and Africans. It is also correlated with breast, gynecological, hepatocellular, lung, oral, and renal cell cancer.

Association between miR-196a-2 Gene Polymorphism and Ovarian Cancer Prognosis in Egyptian Females.

BACKGROUND: Ovarian cancer is the fifth leading cause of cancer-related deaths among women worldwide. Unfortunately, early detection tests are relatively lacking. Diagnosis in the late stages of the disease carries a poor prognosis. OBJECTIVE: To evaluate the relationship between miR-196a-2 rs11614913 polymorphism and ovarian cancer risk and prognosis in Egyptian females. METHODS: In this case-control study, the participants were classified into 2 groups. Group A is the control group which included 50 healthy females. Group B included 50 patients newly diagnosed with ovarian carcinoma confirmed by histopathological analysis. Immunohistochemistry for P53 and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for miR-196a-2 genotypes detection were performed.   Results: There was a statistically significant difference among ovarian cancer cases and controls regarding genotypes (P = 0.003). However, the distribution of the T and C alleles in both studied groups showed no significant difference (P = 0.17). There was a statistically significant increase of CA 125 levels among CT and CC genotypes carriers of ovarian cancer cases (p = 0.04). Besides, there was a statistically significant correlation between miR-196a-2 polymorphism and each of tumor grade (P <0.001), p53 immunohistochemical expression (P= 0.002), and Figo classification (P <0.001). CONCLUSION: There was a statistically significant increase of CA 125 levels among C allele carriers of ovarian cancer cases. Besides, there was a statistically significant association between the miR-196a-2 polymorphism and each of tumor grade, p53 immunohistochemical expression, and Figo classification. So, miR-196a-2 polymorphism can be a possible prognostic factor in ovarian cancer.

Association between Genetic Polymorphisms in MicroRNAs 196a2 (rs11614913) and 34 b/c (rs4938723) and Risk of Hepatocellular Carcinoma in Egyptian Patients.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer with substantial cancer-related deaths worldwide. Deregulation of some genetic polymorphisms has been identified in HCC. OBJECTIVE: We aimed to demonstrate the frequency of miRNA 196a2 rs11614913 and miRNA 34 b/c rs4938723 gene polymorphisms in HCC patients and their correlation with the clinical features and laboratory findings at diagnosis. SUBJECTS AND METHODS: The study was performed on 40 patients with newly diagnosed HCC and 40 patients with liver cirrhosis in addition to 40 age and sex-matched healthy controls. Detection of miRNA 196a2 rs11614913 and miRNA 34 b/c rs4938723 gene polymorphisms was determined by PCR-RFLP. RESULTS: HCC patients had significantly higher frequency of miR-196-2a rs11614913 CC genotype when compared with cirrhotic patients (60.0 % versus 30.0 %, p=0.013). In spite of the fact that HCC patients also had higher frequency of miR-196-2a rs11614913 CC genotype in comparison to controls, the difference fell short of statistical significance (60.0 % versus 42.5 %, p=0.18). No significant differences were found between the studied groups regarding the frequency of miR-196-2a alleles. miR34 b/c rs4938723 CC genotype was the only identified genotype in all participants in the three studied groups. No significant associations were found between the different clinical and laboratory variables and genotypic variations in HCC patients. CONCLUSIONS: This study identified miR-196a2 rs11614913 CC genotype as a risk factor for HCC development while we failed to document similar relation for miR-34b/c rs4938723 polymorphism.

Potential impact of GCK, MIR-196A-2 and MIR-423 gene abnormalities on the development and progression of type 2 diabetes mellitus in Asir and Tabuk regions of Saudi Arabia.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by persistent hyperglycemia and is associated with serious complications. The risk factors for T2DM include both genetic and lifestyle factors. Genome­wide association studies have indicated the association of genetic variations with many diseases, including T2DM. Glucokinase (GCK) plays a key role in the regulation of insulin release in the pancreas and catalyzes the first step in glycolysis in the liver. Genetic alterations in the GCK gene have been implicated in both hyperglycemia and hypoglycemia. MicroRNAs (miRNAs/miRs) are small non­coding RNA molecules that are involved in the important physiological processes including glucose metabolism. In the present study, the association of the single nucleotide polymorphisms (SNPs) in the GCK, MIR­196A­2 and MIR­423 genes with susceptibility to T2DM in patients from two regions of Saudi Arabia were examined, using the tetra­primer amplification refractory mutation system. The results showed that the AA genotype and the A allele of GCK rs1799884 were associated with T2DM [odds ratio (OR)=2.25, P=0.032 and OR=1.55, P=0.021, respectively]. Likewise, the CT genotype and T allele of MIR­196A­2 rs11614913 were associated with an increased risk of T2DM (OR=2.36, P=0.0059 and OR=1.74, P=0.023, respectively). In addition, the CA genotype of MIR­423 rs6505162 C>A was found to be linked with T2DM (OR=2.12 and P=0.021). It was concluded in the present research study that gene variations in GCK, MIR­196A­2 and MIR­423 are potentially associated with an increased risk of T2DM. These results, in the future, may help in the identification and stratification of individuals susceptible to T2DM. Future longitudinal studies with larger sample sizes and in different ethnic populations are recommended to validate these findings.

Association Analysis Between the Functional Single Nucleotide Variants in miR-146a, miR-196a-2, miR-499a, and miR-612 With Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is characterized by an abnormal proliferation of immature lymphocytes, in whose development involves both environmental and genetic factors. It is well known that single nucleotide polymorphisms (SNPs) in coding and noncoding genes contribute to the susceptibility to ALL. This study aims to determine whether SNPs in miR-146a, miR-196a-2, miR-499a, and miR-612 genes are associated with the risk to ALL in pediatric Mexican population. METHODS: A multicenter case-control study was carried out including patients with de novo diagnosis of ALL and healthy subjects as control group. The DNA samples were obtained from saliva and peripheral blood, and the genotyping of rs2910164, rs12803915, rs11614913, and rs3746444 was performed using the 5'exonuclease technique. Gene-gene interaction was evaluated by the multifactor dimensionality reduction (MDR) software. RESULTS: miR-499a rs3746444 showed significant differences among cases and controls. The rs3746444G allele was found as a risk factor to ALL (OR, 1.6 [95% CI, 1.05-2.5]; p = 0.028). The homozygous GG genotype of rs3746444 confers higher risk to ALL than the AA genotype (OR, 5.3 [95% CI, 1.23-23.4]; p = 0.01). Moreover, GG genotype highly increases the risk to ALL in male group (OR, 17.6 [95% CI, 1.04-298.9]; p = 0.00393). In addition, an association in a gender-dependent manner among SNPs located in miR-146a and miR-196a-2 genes and ALL susceptibility was found. CONCLUSION: Our findings suggest that SNP located in miR-499a, miR-146a, and miR-196a-2 genes confer risk to ALL in Mexican children. Experimental analysis to decipher the role of these SNPs in human hematopoiesis could improve our understanding of the molecular mechanism underlying the development of ALL.

Association of miR-146a and miR196a2 genotype with susceptibility to idiopathic recurrent pregnancy loss in Iranian women: A case-control study.

BACKGROUND: Recurrent pregnancy loss (RPL) is the most common complaint of pregnancy in females with a prevalence of 5%. Numerous documents have shown that single nucleotide polymorphisms are able to change miRNA transcription and/or maturation, which may alter the incidence of disorders such as RPL. OBJECTIVE: To assess the relationship of miR-146aC > G (rs2910164) and miR-196a2T > C (rs11614913) with RPL susceptibility in Iranian women. MATERIALS AND METHODS: Blood samples were collected from 214 women who had experienced at least two consecutive spontaneous miscarriages (case) and 147 normal individuals without a history of miscarriage (control). MiR-146aC > G and miR-196a2T > C genotypes were evaluated via the restriction fragment length polymorphism technique. RESULTS: The genotypes incidence did not show a significant difference in pre-miR-146aC > G polymorphism CC vs CG + GG (p = 0.854; OR = 0.933; 95% CI) and CC + CG vs GG (p = 0.282; OR = 1.454; 95% CI). Also, no significant difference was observed between pre-miR-196a2T > C polymorphism TT vs TC + CC (p = 0.862; OR = 0.938; 95% CI) and TT + TC vs CC and (p = 0.291; OR = 1.462; 95% CI) in both the case and control groups. CONCLUSION: The results showed that although the distribution of miR-146aC > G and miR-196a2T > C was different between the unknown RPL and control groups, these variances were not statistically significant.

Deciphering the Variants Located in the MIR196A2, MIR146A, and MIR423 with Type-2 Diabetes Mellitus in Pakistani Population.

MicroRNAs (miRNAs) are small non-coding RNA molecules that control the post-transcriptional gene expression. They play a pivotal role in the regulation of important physiological processes. Variations in miRNA genes coding for mature miRNA sequences have been implicated in several diseases. However, the association of variants in miRNAs genes with Type 2 Diabetes Mellitus (T2DM) in the Pakistani population is rarely reported. Therefore, the current study was designed to investigate the association of rs11614913 T/C (MIR196A2), rs2910164 G/C (MIR146A), and rs6505162 C/A (MIR423) in clinicopathological proven T2DM patients and gender-matched healthy controls. The tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR) reaction method was used to determine the genotypes and to establish the association of each variant with T2DM through inherited models. In conclusion, the present study showed that variants rs11614913 T/C and rs2910164 G/C were linked with the risk of T2DM. The data suggested that rs11614913 T/C and rs2910164 G/C could be considered as novel risk factors in the pathogenesis of T2DM in the Pakistani population.

Upregulation of hsa-miR-196a-5p is associated with MIR196A2 methylation and affects the malignant biological behaviors of glioma.

Hsa-miR-196a-5p is involved in tumorigenesis and progression. However, the driving factors for hsa-miR-196a-5p overexpression and its correlation with the clinicopathological features and prognosis of patients remain unclear in glioma. Thus, this study aimed to investigate the prognostic value of hsa-miR-196a-5p and its correlation with MIR196A2 methylation in glioma. We observed that hsa-miR-196a-5p expression was upregulated in glioma. Next, 112 patients were divided into high (n = 56) and low (n = 56) hsa-miR-196a-5p expression groups. The chi-square test showed that hsa-miR-196a-5p expression was significantly related to age, WHO grade, histopathology, IDH mutation status, and 1p/19q codeletion. Univariate and multivariate Cox regression analyses showed that hsa-miR-196a-5p expression was an independent prognostic factor. GO and KEGG enrichment analyses showed that hsa-miR-196a-5p may be involved in the MAPK signaling, focal adhesion and cancer-related pathways. Compared with the normal astrocyte cell line, glioma cell lines had an unregulated MIR196A2 methylation level, which was confirmed by TCGA data. The hypermethylated CpG sites of MIR196A2 were mainly concentrated in the gene body region, which was significantly associated with hsa-miR-196a-5p overexpression. Kaplan-Meier curves revealed that MIR196A2 hypermethylation was a poor prognostic factor. These findings suggest that hsa-miR-196a-5p overexpression may be involved in malignant biological behaviors, and MIR196A2 hypermethylation of the gene body was significantly associated with hsa-miR-196a-5p overexpression, which was a poor prognostic factor of glioma. Therefore, MIR196A2 hypermethylation may act as an early marker of prognosis of patients with glioma.

miR-499 rs3746444 and miR-196a-2 rs11614913 Are Associated with the Risk of Glioma, but Not the Prognosis.

Previous studies of correlations of microRNA (miR)-499 rs3746444 and miR-196a-2 rs11614913 polymorphisms with glioma risk have yielded inconsistent results. In this study, relationships between these two polymorphisms and glioma risk and survival were evaluated. In total, 605 patients and 1,300 controls were genotyped. rs3746444 increased glioma risk in five genetic models (GA versus AA, odds ratio [OR], 95% confidence interval [CI] = 1.31 [1.05-1.66], p = 0.02; GG versus AA, OR [95% CI] = 10.70 [6.13-18.69], p < 0.0001; GA + GG versus AA, OR [95% CI] = 1.82 [1.47-2.24], p < 0.0001; GG versus AA + GA, OR [95% CI] = 9.99 [5.74-17.40], p < 0.0001; G versus A, OR [95% CI] = 2.18 [1.82-2.60], p < 0.0001). rs11614913 decreased glioma risk in a recessive model (OR [95% CI] = 0.79 [0.64-0.97], p = 0.03). No relationships between either SNP and survival were found. rs3746444 in the miR-499 seed region could affect target recognition. Bioinformatics analyses indicated that miR-499 rs3746444 is involved in various biological processes and pathways, including "cell adhesion molecule binding," "positive regulation of catabolic process," "NF-kappa B pathway," and "PI3K-Akt pathway," by targeting mRNAs. Our results suggested that miR-499 rs3746444 and miR-196a-2 rs11614913 have crucial roles in glioma susceptibility.

The miRNA 196a2 rs11614913 variant has prognostic impact on Turkish patients with multiple myeloma.

OBJECTIVE: Multiple myeloma (MM) arises from malignant plasma cells as a single clone in the bone marrow. Accumulating evidences have reported that there is an association between miR-196a2 (rs11614913) variant and various cancers while there were unverified and inconsistent results in MM. The goal of this study is to investigate the impact of the miR-196a2 variant on clinical findings and susceptibility in MM. Two hundred MM patients (156 patients under transplantation of autologous stem cell) and 200 healthy controls included in this study. RESULTS: The statistical analysis showed no significant relationship for allele and frequencies of miR-196a2 genotype between patients and controls (p > 0.05). Log-rank test showed that gender has highly significant impact on both OS and PFS (p = 0.027, p = 0.045). In the univariate analysis, TT genotype (p = 0.022), and CT/TT (p = 0.008) had better OS. In the multivariate analysis, CC/CT-TT were associated with positively OS (p = 0.041). Currently, the most valuable prognostic markers in MM that has clinical implication are genetic abnormalities. It can be concluded from the results that miR-1962a variant is effective in prognosis of the MM. It is believed that these findings will help us understand the molecular basis of disease.

MiR-196a-2 Genotypes Determine the Susceptibility and Early Onset of Childhood Acute Lymphoblastic Leukemia.

BACKGROUND/AIM: The roles of microRNAs (miRNAs) in tumorigenesis have attracted a lot of attention. The current study aimed at examining the association of the miR-196a-2 rs11614913 genotypes with susceptibility to childhood acute lymphoblastic leukemia (ALL) in Taiwan. MATERIALS AND METHODS: This case-control investigation recruited 266 patients with childhood ALL and 266 healthy controls, and the miR-196a-2 rs11614913 genotypes of each participant were examined via the polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The frequency of miR-196a-2 C allele in controls was 0.440 compared with 0.423 in ALL patients. In addition, there was no significant association between CT or CC genotypes with susceptibility to childhood ALL (OR=0.89 and 0.89, 95%CI=0.60-1.30 and 0.54-1.45, p=0.5427 and 0.6302). Furthermore, the frequencies of miR-196a-2 polymorphisms were not associated with age, gender and clinical outcomes in ALL cases. CONCLUSION: The miR-19a-2 genotypes are not associated with susceptibility to childhood ALL in Taiwan.

The polymorphism of rs11614913 T/T in pri-miR-196a-2 alters the miRNA expression and associates with recurrent spontaneous abortion in a Han-Chinese population.

Rs11614913 in pri-miR-196a-2 is involved in the occurrence of many diseases, especially in cancers. However, it remains unknown whether miR-196a-2 is associated with human recurrent spontaneous abortion (RSA) in Chinese Han population. Our study found that rs11614913 T/T in pri-miR-196a-2 was associated with the increase risk of human unexplained RSA (URSA) in recessive mode in Chinese Han population. The T allele of rs11614913 increased the production of mature miR-196a-3p. Rs11614913 T/T inhibited HTR-8/SVneo cells proliferation and migration and promoted cells apoptosis. Further investigation discovered that dihydrofolate reductase (DHFR) was the target of miR-196a-3p and inversely regulated by miR-196a-3p. Dual-luciferase assay indicated that T allele in miR-196a-2 rs11614913 could more effectively suppress DHFR expression than C allele. In addition, C to T substitution in miR-196a-2 rs11614913 attenuated the sensibility of cells to mifepristone. Collectively, our data suggest that miR-196a-2 rs11614913 T/T in pri-miR-196a-2 may be conductive to the genetic predisposition to RSA by disrupting the production of mature miR-196a-3p and reinforcing the expression of DHFR.

Evaluation of miR-196a2 expression and Annexin A1 level in children with bronchial asthmaEvaluation of miR-196a2 expression and Annexin A1 level in children.

BACKGROUND: Annexin A1 (ANXA1) is an important anti-inflammatory mediator that may play a significant role in bronchial asthma. MiR-196a2 can target ANXA1 and therefore may play a role in the pathogenesis of asthma. AIM OF STUDY: This is the first study which aimed to evaluate the expression of miR-196a2 in the serum of asthmatic children and correlate its expression with ANXA1 serum level and asthma severity. SUBJECTS AND METHODS: The study included 100 asthma patients who were subdivided into three groups (mild, moderate and severe) and 50 healthy control subjects. Assessment of miR-196a2 expression and ANXA1 serum level were done using quantitative reverse transcriptase PCR (RT qPCR) and Elisa techniques, respectively. RESULTS: Compared to the control group, asthmatic children showed an increased ANXA1 serum level and decreased expression of miR-196a2 (p=0.001). However, ANXA1 serum level was lower and miR-196a2 expression was higher in severe asthmatic patients compared to moderate asthmatic ones (p=0.01, 0.03). Pearson's correlation coefficient revealed no significant correlations between ANXA1 serum level and miR-196a2 expression in the patient group (p=0.9). CONCLUSIONS: Altered miR-196a2 expression and serum ANXA1 concentration may play a role in the pathogenesis of asthma. In addition, ANXA1 and miR-196a2 may represent potential diagnostic biomarkers for asthma and future targets for therapy.

Predictive role of single nucleotide polymorphism (rs11614913) in the development of breast cancer in Pakistani population.

Aim: miRNAs play an important role in breast cancer (BC). Variations in miRNAs influence their maturation, expression and consequently regulation of their target genes. Materials & methods: In this study, single nucleotide polymorphism rs11614913 was genotyped in BC patients (n = 300) and 230 controls by employing tetra primer amplification refractory mutation system PCR and Sanger sequencing (Macrogen Korea). Results: A significant difference was observed in the genotypes through co-dominant (χ2.#x00A0;= 42.03; p < 0.0001), additive (odds ratio [OR] = 0.6441 [0.4887-0.8490, 95% confidence interval]; p < 0.0019), dominant (OR = 0.3996 [0.2809-0.5686], p < 0.0001) and recessive (OR = 0.2993 [0.1220-0.7347], p < 0.009) statistical models showed decreased risk association of C allele with BC. Conclusion: Females having CT genotype are at higher risk of BC as compared with those having CC genotype.

Association of MicroRNA 196a and 499 Polymorphisms with Development of Cirrhosis and Hepatocellular Carcinoma Post-HCV Infection in Egyptian Patients.

Hepatocellular carcinoma (HCC) is the commonest primary tumor of the liver. Chronic HCV infection is the leading cause of end-stage liver disease, HCC and liver-related death in Egypt. Single nucleotide polymorphisms (SNPs) in microRNAs were reported to increase susceptibility to tumorigenesis; affect prognosis and as promising biomarkers in virus-host interactions. This study was conducted to investigate the role of genetic variants of miR-196a2 (rs 11614913) C>T and miR-499 (rs 3746444) A>G in the development of cirrhosis and HCC in Egyptian HCV infected patients. Genotyping of the candidate SNPs was performed by Real Time PCR in 75 HCV-related HCC patients, 75 cirrhotic patients on top of HCV and 75 healthy controls. There was significant difference in miR-499 (rs3746444) genotypes frequency between the three studied groups as the GG genotype was significantly lower in HCC cases than other groups (P = 0.009) while the combined miR-499 (AA+AG) genotypes were significantly higher in HCC cases than other groups (P = 0.005). Also a significant difference was found in miR-499 genotypes frequency when compared between HCC and cirrhosis groups as the GG genotype was significantly lower in HCC cases than cirrhosis group (P = 0.006) while the combined miR-499 (AA+AG) genotypes were significantly higher in HCC cases than in cirrhosis group (P = 0.003) [OR (95% CI) = 0.131 (0.028-0.601)]. The frequency of the G allele was significantly lower in HCC than other groups (P = 0.024) and significantly lower in HCC than normal group (P = 0.006) [OR (95%CI) = 0.501 (0.304-0.825)]. For miR-196a2 (rs11614913) C>T polymorphisms, no significant association was found with HCC risk. Our study concluded that the G allele of miR-499 is associated with lower risk of HCV related HCC development. No significant association of miR-196a2 (rs 11614913), genotypes or alleles with risk for HCC development, could be detected.
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Association between miR-146a C > G, miR-149 T > C, miR-196a2 T > C, and miR-499 A > G polymorphisms and susceptibility to idiopathic recurrent pregnancy loss.

BACKGROUND: A growing body of evidence suggests that microRNAs play fundamental regulatory roles in embryo implantation and maintenance of pregnancy. The aim of this study was to investigate the possible association between miR-146a C > G, miR-149 T > C, miR-196a2 T > C, and miR-499 A > G polymorphisms and genetic susceptibility to recurrent pregnancy loss (RPL). MATERIAL AND METHODS: One hundred and twenty women with a history of two or more unexplained consecutive miscarriages and 90 ethnically matched healthy women with a history of at least two successful pregnancy outcomes and without a history of miscarriage were enrolled in a case-control study. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Our findings showed that the prevalence of miR-149 T > C polymorphism in RPL patients was significantly higher than those in healthy controls (p < 0.05). We also found that the presence of miR-149 C and miR-499 G alleles was significantly associated with susceptibility to RPL (p < 0.05). The miR-146a CC/miR-499 GG, miR-149 TC/miR-499 AG, and miR-196a2 TT/miR-499 GG combined genotypes were associated with the high risk of RPL (p < 0.05). CONCLUSION: This study suggests that miR-149 T > C polymorphism and the presence of miR-149 C, and miR-499 G alleles are a genetic determinant for the risk of idiopathic RPL.