miRNA Machinery Genes Research Articles

Pan-Cancer Study on Variants of Canonical miRNA Biogenesis Pathway Components: A Pooled Analysis.

Single nucleotide polymorphisms in genes involved in microRNA processing/maturation and release may deregulate the microRNAome expression levels. We aimed to assess the relationship between miRNA machinery genetic variants and human cancer risk using integrative bioinformatics analyses to identify the role of these genes in cancer aggressiveness. Mutations of 8176 pan-cancer samples were retrieved from 33 studies in "TCGA" database, and a Cox regression model for survival was performed. Next, 22 computationally identified variants within 11 genes were selected based on their high citation rate and MAF. Relevant articles through March 2020 were included. Pooled estimates under the five genetic association models were calculated. Publication bias and heterogeneity between articles were evaluated. Trial Sequential Analysis (TSA) was applied to assess the power and reliability of the draw conclusions. TCGA patients with different cancer types revealed significant alterations in miRNA machinery genes, with mutation frequency ranging from 0.6-13% of samples. RAN was associated with LN metastasis, while TARBP2 and PIWIL1 gene mutations exhibited better overall survival. In the meta-analysis, 45 articles (74,593 cases and 89,198 controls) met the eligibility criteria. Pooled analysis revealed an increased cancer risk with DROSHArs10719*G, RANrs3803012*G, DGCR8rs417309*A, and GEMIN3rs197414*A. In contrast, both DICER1rs1057035*T and GEMIN4rs2743048*G conferred protection against developing cancer. TSA showed the cumulative evidence is inadequate, and the addition of further primary studies is necessary. This study suggests a potential role of miRNA biogenesis genes in cancer development/prognosis. Further functional studies may reveal biological explanations for the differential risks of the machinery variants in different cancer types.

Individual and joint effects of genetic polymorphisms in microRNA-machinery genes on congenital heart disease susceptibility.

Single-nucleotide polymorphisms in miRNA-machinery genes may alter the biogenesis of miRNAs affecting disease susceptibility. In this case-control study, we aimed to evaluate the impact of three single-nucleotide polymorphisms (DICER rs1057035, DROSHA rs10719, and XPO5 rs11077) and their combined effect in a genetic risk score model on congenital heart disease (CHD) risk. A total of 639 participants was recruited, including 125 patients with CHD (65 males; age 9.2 ± 10 years) and 514 healthy controls (289 males; age 15.8 ± 18 years). Genotyping of polymorphisms in miRNA-machinery genes was performed using a TaqMan®SNP genotyping assay. A genetic risk score was calculated by summing the number of risk alleles of selected single-nucleotide polymorphisms. There was a significantly increased risk of CHD in patients with XPO5 rs11077 CC genotype as compared to AC heterozygote and AA homozygote patients (ORadjusted = 1.7; 95% CI: 1.1-2.8; p = 0.018). A clear tendency to significance was also found for DROSHA rs10719 AA genotype and CHD risk for both codominant and recessive models (ORadjusted = 1.8; 95% CI: 0.91-3.8; p = 0.09 and ORadjusted = 1.9; 95% CI: 0.92-4; p = 0.08, respectively). The resulting genetic risk score predicted a 1.73 risk for CHD per risk allele (95% CI: 1.2-2.5; p = 0.002). Subjects in the top tertile of genetic risk score were estimated to have more than three-fold increased risk of CHD compared with those in the bottom tertile (ORadjusted = 3.52; 95% CI: 1.4-9; p = 0.009). Our findings show that the genetic variants in miRNA-machinery genes might participate in the development of CHD.

Genetic polymorphisms of miRNA machinery genes in bicuspid aortic valve and associated aortopathy.

Aim: SNPs in miRNA machinery genes may affect miRNA function by impacting their biogenesis. Here, we investigated the association between three SNPs in miRNA machinery genes (DICER rs1057035, DROSHA rs10719 and XPO5 rs11077) and bicuspid aortic valve (BAV). Materials & methods: Three polymorphisms were analyzed in 177 BAV patients and 414 healthy subjects by using a TaqMan®SNP assay. Results: The frequencies of XPO5 rs11077 genotype were significantly different between BAV patients and controls (p=0.022). On multivariate logistic regression analysis, the XPO5 rs11077 C allele resulted a significant predictor of BAV (odds ratioadjusted=0.65; CI: 0.42-0.98; p=0.047). Conclusion: The XPO5 rs11077 SNP was associated with a decreased BAV risk supporting the causative role of miRNAs in aortic valve development.

Association between Genetic Polymorphisms in microRNA Machinery Genes and Risk of Papillary Thyroid Carcinoma.

Evidence suggests that the microRNAs are involved in tumorigenesis and progression of various types of malignant tumors. Therefore, the aim of current research was to examine association between genetic variants in the miRNA machinery genes and risk of papillary thyroid carcinoma(PTC) in Iranian population. Peripheral blood samples were collected from 120 PTC patients and 130 healthy subjects. Genotyping of polymorphisms in miRNA Machinery genes (DICER1 rs3742330, DROSHA rs6877842 and XPO5 rs11077) polymorphisms was performed using PCR-RFLP method. Chi square and independent sample t tests were applied for categorical and continuous variables, respectively. In this study, we found that frequency of DICER1 rs3742330G allele was significantly higher in controls compared to PTC patients. In addition, the DICER1 rs3742330 polymorphism was associated with lower risk of PTC in dominant (AG + GG vs. AA, OR = 0.5, 95%CI = 0.3-0.9, P = 0.03) model. No association was found between DROSHA rs6877842 and XPO5 rs11077 polymorphisms and PTC neither in dominant nor in recessive and allelic models. The frequency of DROSHA rs6877842GC genotype was higher in PTC patients with smaller tumor size (<1). Therefore, this polymorphism could be a protective factor for tumor development in PTC patients (OR = 0.3, 95%CI = 0.1-1, P = 0. 04). The current study indicated that DICER1 rs3742330 polymorphism was associated with lower risk of PTC. Furthermore, DROSHA rs6877842 polymorphism could be a protective factor for tumor development in PTC patients.

Low Drosha protein expression in cutaneous T-cell lymphoma is associated with worse disease outcome.

Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types. We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL). We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed. On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P=0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P=0.017 and P=0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P=0.032) and DSD (P=0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P=0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P=0.026) and elevated LDH (P=0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively). Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.

Influence of genetic polymorphisms in DICER and XPO5 genes on the risk of coronary artery disease and circulating levels of vascular miRNAs

IntroductionSingle-nucleotide polymorphisms (SNPs) in microRNA (miRNA) machinery genes may affect the regulatory capacity of miRNAs by impacting their biogenesis. The aim of the study was to analyze the association between SNPs in two key genes (DICER rs1057035T>C and XPO5 rs11077A>C) and coronary artery disease (CAD) risk as well as to examine their effects on circulating levels of vascular miRNAs. Materials and methodsWithin the Italian GENOCOR cohort, we studied a cohort of 557 patients (502 males, 57 ± 9 years) with angiographically documented CAD. A total of 443 healthy controls (262 males, 56 ± 12 years) was also enrolled. Genotyping was determined by using a TaqMan®SNP genotyping assay. Analysis of miR-132 and miR-140-3p was assessed in a subset of 70 CAD patients by using qRT-PCR. ResultsThere were statistically significant differences between CAD patients and healthy controls in the distribution of both DICER and XPO5 genotypes (p = 0.03 and p = 0.02, respectively). Multivariate analysis showed a significantly decreased risk of CAD by 50% in patients with DICER rs105703CC genotype as compared to TC heterozygote and TT homozygote patients (ORadjusted = 0.50; CI: 0.30–0.83, p = 0.007). In a recessive model, the XPO5 rs11077CC genotype was associated with a 32% reduced risk of CAD (ORadjusted = 0.68; CI: 0.30–0.99 p = 0.047). XPO5 rs11077CC genotype was significantly associated with higher levels of both miRNA-132 (p = 0.04) and miRNA-140-3p (p = 0.03). ConclusionsGenetic polymorphisms in DICER and XPO5 genes are associated with a decreased risk of CAD, probably by impacting expression levels of vascular and cardiac-specific miRNAs. Further studies are needed to better elucidate the biological relevance of both variants in CAD development.

Genetic variants in DICER1, DROSHA, RAN, and XPO5 genes and risk of pregnancy-induced hypertension.

To evaluate the impact of microRNA (miRNA) machinery gene polymorphisms on the risk of gestational hypertension (GH) and preeclampsia (PE). A case-control study among Han Chinese with a total of 143 patients diagnosed with PE, 79 with GH, and 330 healthy controls was conducted. Nine candidate SNPs in 4 selected miRNA biogenesis genes were genotyped, including three DICER1 SNPs (rs3742330, rs1057035 and rs13078), two DROSHA SNPs (rs17409893 and rs642321), two RAN SNPs (rs3803012 and rs14035), and two XPO5 SNPs (rs1106841 and rs2257082). Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CIs) for the associations. The DICER1 rs13078 TA genotype was still strongly associated with an increased risk of GH (OR = 3.17 (95% CI: 1.55, 6.48)), and the RAN rs3803012 AG genotype was associated with an increased risk of PE (OR = 2.15 (1.26, 3.66)). The RAN rs14035/rs3803012 haplotype C-G was associated with PE susceptibility (OR = 2.08 (95% CI: 1.19, 3.62)); however, the haplotype C-A was a protective factor for PE (OR = 0.68 (95% CI: 0.50, 0.93)). The DICER1 rs1057035/ rs13078/ rs3742330 haplotype T-A-A and DORSHA rs17409893/rs642321 haplotype A-T were both associated with increased risk of GH (OR = 2.75 (95% CI:1.40, 5.38) and OR = 1.60 (95% CI:1.12, 2.29), respectively). These significant associations were retained after false-positive discovery rate correction (p < 0.05). Genetic variants in miRNA machinery genes might participate in the development of pregnancy-induced hypertension. The DICER1 rs1078 polymorphism is associated with GH and the RAN rs3803012 polymorphism is associated with PE.

MicroRNA Biogenesis Pathway Gene Polymorphisms Are Associated with Breast Cancer Risk

MicroRNAs (miRNAs) play an important role as epigenetic regulators in cancer initiation and progression. One of the mechanisms of miRNA dysregulation is altered functioning of proteins involved in miRNA processing machinery. It has been suggested that single nucleotide polymorphisms (SNPs) within miRNA gene regions, miRNA target genes, and miRNA machinery genes may affect the miRNAs regulation. We selected 25 SNPs in the key genes of miRNA biosynthesis, including DROSHA/RNASEN, DGCR8, DICER1, XPO5, RAN, PIWIL1/HIWI, AGO1/EIF2C1, AGO2, GEMIN4, GEMIN3/DDX20, and DDX5, and investigated the association between these SNPs and the risk of breast cancer. The total number of breast cancer cases and cancer-free controls enrolled in the investigation were 778 (417 breast cancer patients and 361 healthy women). We found that rs11060845 and rs10773771 in the PIWIL1 gene, rs3809142/RAN, rs10719/DROSHA, rs1640299/DGCR8, rs563002/DDX20, rs595055/AGO1, and rs2740348/GEMIN4 were associated with breast cancer risk in Russians.

Genetic variants in miRNA machinery genes associated with clinicopathological characteristics and outcomes of gastric cancer patients.

Polymorphisms in miRNA machinery genes have been proved to be related to risk or survival of several kinds of cancers, but the results are controversial and the role of these polymorphisms in gastric cancer remains uncertain. In our study, we investigated the association between five genetic variants in miRNA machinery genes ( DICER, RAN, XPO5 [name of the gene]) and clinical outcomes in Chinese gastric cancer patients. A total of 96 patients with stage IB-III gastric cancer treated with radical gastrectomy and adjuvant chemotherapy of oxaliplatin and fluorouracils were analyzed. The MassARRAY MALDI-TOF system was used to determine the genotypes. DICER rs3742330 AG+GG genotype was associated with more advanced T stage compared to AA genotype ( P=0.009). More patients with XPO5 rs2257082 CC genotype had poorly differentiated tumors compared with CT+TT genotype carriers. After adjustment by age, sex, differentiation, T stage, and lymph node status, XPO5 rs2257082 CC genotype carriers were found to have worse disease-free survival than CT+TT genotype carriers (adjusted HR 3.099; 95% CI 1.270, 7.564; P=0.013), carriers of RAN rs14035 CC genotype had higher three-year OS rate than carriers of CT+TT genotype (adjusted HR 3.174; 95% CI 1.010, 9.973; P=0.048). These results indicated that genetic variants in miRNA machinery genes might be associated with the clinicopathological features and prognosis of completely resected gastric cancer patients.

Dicer1, AGO3, and AGO4 microRNA machinery genes are differentially expressed in developing female reproductive organs and overexpressed in cancerous ovaries of chickens.

MicroRNA (miRNA)-mediated gene silencing is a key mechanism regulating numerous biological processes such as development of organs and tumorigenesis. The expression of miRNA machinery genes linked to miRNA biogenesis and processing is finely regulated. Despite accumulating evidence for chicken miRNA in the female reproduction system, precise regulatory mechanisms are largely unknown. Therefore, the objective of this study was to determine changes in expression levels of miRNA machinery genes in developmental stages of the oviduct and ovarian carcinogenesis of laying hens. In the present study, differential expression of miRNA machinery genes during ovarian carcinogenesis was determined using cancerous and normal ovaries collected from normal laying hens and hens with cancer. Our results showed that 3 miRNA machinery genes (, , and ) were differentially expressed as laying hens' reproductive organs developed. These genes were simultaneously upregulated in cancerous ovaries compared with those in normal ovaries. Their transcripts were abundantly localized in glandular epithelial cells of cancerous ovaries. Our results indicate that , , and play critical roles in the development of reproductive organs and ovarian carcinogenesis in laying hens, suggesting that simultaneous overexpression of these genes might serve as a prognostic factor for ovarian cancer.

Association between SNPs in microRNA machinery genes and gastric cancer susceptibility, invasion, and metastasis in Chinese Han population.

ObjectiveThe present study investigates the influence of genetic variants in miRNA machinery genes (DROSHA, DICER, AGO1, and GEMIN4) on gastric cancer in Chinese Han population, further revealing the genetic mechanisms of gastric cancer occurrence and development.MethodsGenotyping of single nucleotide polymorphisms (SNPs) was performed in 628 patients with GC and 502 frequency-matched (age and gender) controls by the high resolution melting (HRM) method.ResultsThe SNPs rs3742330 (DICER) and rs7813 (GEMIN4) were associated with susceptibility to gastric cancer (P = 0.002 and 0.010, respectively). Stratified analysis showed that the G allele of rs3742330 and genotype TT as well as T allele of rs7813 were associated with a later stage of gastric cancer (P=0.027, 0.032 and 0.018, respectively). Furthermore, the genotype TT and T allele of rs7813 appeared to be associated with a higher level of lymphatic metastasis of gastric cancer (P=0.021 and 0.030, respectively), while the genotype AA and A allele of rs636832 (AGO1) were correlated with a lower level of lymphatic metastasis of gastric cancer (P=0.016 and 0.041, respectively). There was no significant association between rs10719 (DROSHA) and gastric cancer.ConclusionThe present data demonstrated that genetic variants in miRNA machinery genes had a significant association with GC susceptibility (DICER and GEMIN4) and malignant behavior such as tumor stage (DICER and GEMIN4) and lymphatic metastasis of GC (GEMIN4 and AGO1) in Chinese Han population.

MicroRNA-16 Modulates Melatonin-Induced Cell Growth in the Mouse-Derived Spermatogonia Cell Line GC-1 spg Cells by Targeting Ccnd1.

Melatonin exerts a range of physiological effects. However, the functional significance of melatonin in spermatogenesis and the underlying mechanisms remain unclear. MicroRNAs (miRNAs) are essential in the initiation and progression of testicular development, including spermatogenesis. Thus far, limited information is known about the role of miRNAs in melatonin-mediated spermatogenesis. In this study, the expression levels of testicular miRNA machinery genes, namely, Dgcr8 and Xpo5, were significantly increased by melatonin. The miRNA expression profile was identified in the testes of melatonin-treated mice. Ten miRNAs were significantly up-regulated, and 15 miRNAs were down-regulated. Melatonin (25 μM) enhanced cell growth and reduced apoptosis in GC-1 spg cells. Among the down-regulated miRNAs, miR-16 expression was influenced by melatonin in GC-1 spg cells. The miR-16 mimics in GC-1 spg cells significantly suppressed cell growth and promoted cell apoptosis. Conversely, transfection of the miR-16 inhibitor significantly increased cell growth and decreased cell apoptosis. The protein expression level of CCND1 (Cyclin D1) in GC-1 spg cells was decreased by the miR-16 mimics and increased by knockdown of miR-16. Moreover, bioinformatics and reporter activity analyses showed that Ccnd1 was a potential target of miR-16. These results suggested that miR-16 may function as a novel regulator of testicular functions during melatonin stimulation by targeting Ccnd1.

The rs61764370 Functional Variant in the KRAS Oncogene is Associated with Chronic Myeloid Leukemia Risk in Women

Chronic myeloid leukemia (CML) is one of the most frequent hematopoietic malignancies in the elderly population; however, knowledge is limited regarding the genetic factors associated with increased risk for CML. Polymorphisms affecting microRNA (miRNA) biogenesis or mRNA:miRNA interactions are important risk factors in the development of different types of cancer. Thus, we carried out a case-control study to test the association with CML susceptibility of gene variants located in the miRNA machinery genes AGO1 (rs636832) and GEMIN4 (rs2740348), as well as in the miRNA binding sites of the genes BRCA1 (rs799917) and KRAS (rs61764370). We determined the genotype of 781 Mexican-Mestizo individuals (469 healthy subjects and 312 CML cases) for the four polymorphisms using TaqMan probes to test the association with CML susceptibility. We found a borderline association of the minor homozygote genotype of the KRAS_rs61764370 polymorphism with an increased risk for CML susceptibility (P = 0.06). After gender stratification, this association was significant only for women (odds ratio [OR] = 13.41, P = 0.04). The distribution of the allelic and genotypic frequencies of the four studied SNPs was neither associated with advanced phases of CML nor treatment response. To the best of our knowledge, this study is the first to show a significant association of the KRAS_rs61764370 SNP with CML. To further determine such an association of with CML susceptibility, our results must be replicated in different ethnic groups.

Single nucleotide polymorphisms of microRNA processing genes and outcome of non-Hodgkin's lymphoma.

ObjectivemicroRNA (miRNA)-related single nucleotide polymorphisms (miR-SNPs) in miRNA-processing machinery genes can affect cancer risk, treatment efficacy, and patients’ prognosis by mediating the expression of targeted genes. Five miR-SNPs in miRNA processing machinery genes, including XPO5 (rs11077), RAN (rs14035), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348), in 168 non-Hodgkin’s lymphoma (NHL) patients were evaluated for their association with the cancer risk and outcomes associated with NHL.Materials and methodsmiR-SNPs were genotyped using polymerase chain reaction–ligase detection reaction. The survival curves were calculated using the Kaplan–Meier method, and comparisons between the curves were made using the log-rank test. Multivariate survival analysis was performed using a Cox proportional hazards model.ResultsAmong the five SNPs, only rs197412 located in the coding region of the GEMIN3 gene was identified; it was independently associated with overall survival in NHL patients, as determined by multivariate analysis (relative risk: 1.649; 95% confidence interval: 1.110–2.449; P=0.013). The prognostic value of this miR-SNP in patient outcomes was also observed in the diffuse large B-cell lymphoma and T-cell lymphoma NHL subtypes.ConclusionOur results suggested that the specific genetic variants observed in the miRNA machinery genes may affect NHL survival.

Single-nucleotide polymorphisms of microRNA processing machinery genes and risk of colorectal cancer.

ObjectiveMicroRNA (miRNA)-related single-nucleotide polymorphisms (miR-SNPs) in miRNA processing machinery genes can affect cancer risk, treatment efficacy, and patient prognosis. We genotyped 6 miR-SNPs of miRNA processing machinery genes including XPO5 (rs11077), RAN (rs14035), Dicer (rs3742330), TNRC6B (rs9623117), GEMIN3 (rs197412), and GEMIN4 (rs2740348) in a case-control study to evaluate their impact on colorectal cancer (CRC) risk.Materials and methodsmiR-SNPs were genotyped using the polymerase chain reaction– ligase detection reaction. The χ2 test was used to analyze dichotomous values, such as the presence or absence of any individual SNP in CRC patients and healthy controls.ResultsTwo of these SNPs were identified for their association with cancer risk in the Dicer and GEMIN3 genes. The AA allele of rs3742330 located in the Dicer gene exhibited a significantly increased risk of CRC (odds ratio, 2.11; 95% confidence interval: 1.33–3.34; P=0.001); the TT allele of rs197412 located in GEMIN3 also exhibited a significantly increased risk of CRC (odds ratio, 1.68; 95% confidence interval: 1.07–2.65; P=0.024).ConclusionOur results suggest that the specific genetic variants in miRNA machinery genes may affect CRC susceptibility.

MicroRNA related polymorphisms and breast cancer risk.

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.

Association between SNPs in miRNA-machinery genes and chronic hepatitis B in the Chinese Han population

Single nucleotide polymorphisms (SNPs) in miRNA-machinery genes can influence their generation and maturation, then expression and structure. To explore the relationship between three SNPs (rs3757 in DGCR8, rs636832 in AGO1, rs7813 in GEMIN4) in miRNA-machinery genes and chronic hepatitis B, we genotyped the SNPs by high resolution melting method (HRM) in a case-control study of 332 unrelated chronic hepatitis B patients and 352 unrelated healthy controls in Western China. Interestingly, the rs636832 was significantly associated with the susceptibility of CHB (genotype: AA/GA/GG: p=0.010; allele: A/G: OR=0.727, 95% CI=0.575–0.920, p=0.008). The minor allele A of rs636832 was significantly associated with a decreased risk of CHB. Additionally, the dominant model AG+GG vs. AA showed a risk of 1.442-fold (p=0.018) with CHB. Further exploration for the association between rs636832 and HBV-DNA load in 329 cases showed no significant difference (genotype: p=0.321; allele: p=0.148). Neither did the association between rs636832 and the status of HBsAg and HbeAg (HBsAg: genotype p=0.337, allele p=0.436; HBeAg: genotype p=0.861, allele p=0.822). Our study first provided the evidence that rs636832 in AGO1 was associated with chronic HBV infection susceptibility in Chinese Han population. Further epidemiological and functional studies in larger populations are warranted to verify our results.

MicroRNA Machinery Genes as Novel Biomarkers for Cancer.

MicroRNAs (miRNAs) directly and indirectly affect tumorigenesis. To be able to perform their myriad roles, miRNA machinery genes, such as Drosha, DGCR8, Dicer1, XPO5, TRBP, and AGO2, must generate precise miRNAs. These genes have specific expression patterns, protein-binding partners, and biochemical capabilities in different cancers. Our preliminary analysis of data from The Cancer Genome Atlas consortium on multiple types of cancer revealed significant alterations in these miRNA machinery genes. Here, we review their biological structures and functions with an eye toward understanding how they could serve as cancer biomarkers.

Genetic Variants in MicroRNA Machinery Genes Are Associate with Idiopathic Recurrent Pregnancy Loss Risk

ObjectiveKey molecules involved in microRNA (miRNA) biogenesis, such as DROSHA, XPO5, and DICER, have been identified in trophoblast cells, confirming that the miRNA biogenesis pathway is active in human placenta. In addition, miRNAs regulate uterine gene expression associated with inflammatory responses during the peri-implantation period and participate in maternal-fetal immune tolerance. The purpose of this study was to demonstrate whether genetic polymorphisms in miRNA machinery genes show an association with idiopathic recurrent pregnancy loss (RPL) in Korean women.Study designWe performed a case-control study with 238 controls and 338 women who had experienced at least two consecutive pregnancy losses between 1999 and 2010. Genotypes of miRNA machinery genes, including DICER rs3742330, DROSHA rs10719, RAN GTPase (RAN) rs14035, and exportin-5 (XPO5) rs11077 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The logistic odds ratios (ORs) of RPL were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. Gene-gene interactions among the loci of the four gene polymorphisms were evaluated using the multifactor dimensionality reduction (MDR) method.ResultsThe RAN rs14035 CC genotype and DICER rs3742330/DROSHA rs10719 GG/TC+CC, rs3742330/RAN rs14035 GG/CC, and DICER rs3742330/XPO5 rs11077 GG/AC+CC combinations were significantly associated with increased RPL risk, whereas the RAN rs14035 CT, DICER rs3742330/RAN rs14035 AA+AG/CT+TT, DROSHA rs10719/RAN rs14035 TC+CC/CT+TT, and RAN rs14035/XPO5 rs11077 CT+TT/AA combinations reduced RPL risk. The A-T-T-C and G-C-T-A allele combinations (DICER/DROSHA/RAN/XPO5) were 20 times more frequent in the RPL group than in the control group.ConclusionOur study demonstrates the relationship between RPL development and the polymorphism of the miRNA machinery gene RAN and combined genotype of DROSHA/DICER.

Systematic association analysis of microRNA machinery genes with schizophrenia informs further study

microRNAs (miRNAs) play a vital role in development via the post-transcriptional regulation of most genes. Variation in the miRNA machinery pathway proteins which mediate the biogenesis, maturation, transportation, and functioning of miRNAs might be relevant to human traits. In this work, we explored the role of 59 miRNA machinery genes in schizophrenia (SZ). Association analysis of 967 single nucleotide polymorphisms within these genes detected that an intronic polymorphism of EIF4ENIF1, rs7289941, was significantly associated with SZ (P=4.10E−5). We failed to replicate this result in a validation sample comprising 1027 healthy controls and 1012 SZ cases, and the combined data yielded nominal significance (P=0.013). We conducted a gene-based association analysis using VEGAS and SKAT, and found seven associated genes in total, including EIF4ENIF1, PIWIL2, and DGCR8, but none survived correction for multiple testing. Taken together, our data do not provide strong support for the association of common variants within miRNA machinery genes with SZ in the Han Chinese population, but implicate several promising candidate genes for further research.