RESUMEN
Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.
Asunto(s)
Autofagia , Retículo Endoplásmico , Preeclampsia , Proteínas Proto-Oncogénicas c-akt , ARN Largo no Codificante , Transducción de Señal , Serina-Treonina Quinasas TOR , Trofoblastos , Adulto , Animales , Femenino , Humanos , Embarazo , Ratas , Autofagia/genética , Línea Celular , Movimiento Celular/genética , Proliferación Celular/genética , Retículo Endoplásmico/metabolismo , Placenta/metabolismo , Preeclampsia/metabolismo , Preeclampsia/genética , Preeclampsia/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Serina-Treonina Quinasas TOR/metabolismo , Trofoblastos/metabolismo , Trofoblastos/patología , MasculinoRESUMEN
Traumatic brain injury (TBI) causes high rates of worldwide death and morbidity because of the complex secondary injury cascade. Circular ribonucleic acid (RNA) (circRNA), a type of RNA that forms a covalently closed continuous loop, may be involved in the regulation of secondary injury because it is expressed widely in the brain and contributes to a large class of post-transcriptional regulators. Deep RNA sequencing (RNA-seq) and bioinformatic analysis were performed to investigate the expression profile and function of circRNAs in the mouse cortex after controlled cortical impact (CCI). A total of 19,794 circRNAs were identified, and 1315 were annotated in circBase. There were 191 filtered differentially expressed circRNAs (98 for up-regulated and 93 for down-regulated). The gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that inflammation, cell death, and repair of damage were the main biological processes and molecular mechanisms related to altered circRNAs. The pathway-circRNA interaction network revealed three core circRNAs and five corepathways related to TBI. The circRNA-messenger RNA (mRNA) interaction network and competitive endogenous RNA (ceRNA) analysis suggested potential microRNA (miRNA) sponges and target mRNAs. In addition to five optimal circRNA-miRNA-mRNA pairs were analyzed, circRNA_16895-miRNA myosin-10 (Myo 10) was predicted to regulate fragment crystallizable gamma receptors (FcγR)-mediated phagocytosis pathway. Four circRNAs were selected for quantitative real-time polymerase chain reaction analysis to validate the sequencing data. Our results provide promising functions of circRNAs aberrantly expressed in TBI to explore molecular mechanisms and potential therapeutic targets for its therapy.
Asunto(s)
Lesiones Traumáticas del Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Regulación de la Expresión Génica , ARN Circular/metabolismo , Animales , Lesiones Traumáticas del Encéfalo/genética , Perfilación de la Expresión Génica , Masculino , Ratones , ARN Circular/genética , TranscriptomaRESUMEN
Previous studies have demonstrated that miR-34 family members are abnormally expressed in gastric cancer. Overexpression of the miR-34 family suppresses gastric carcinogenesis, whereas downregulation of the miR-34 family promotes tumorigenesis. p53 can bind to the promoter region of miR-34b/c, leading to an increase of miR-34b/c expression. Recently, a variant in the promoter region of pri-miR-34b/c (rs4938723) has been discovered, with the function of altering the binding efficiency of transcription factor GATA. The purpose of this study was to examine the role of the miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms in the susceptibility of gastric cancer. We analyzed the distribution of the two polymorphisms in 197 patients with gastric cancer and 289 age-, gender-, ethnicity-, and living area-matched controls using polymerase chain reaction-restriction fragment length polymorphism and DNA direct sequencing. We found that the CT and CT/CC genotypes of the miR-34b/c rs4938723 were associated with a significantly decreased risk of gastric cancer compared with the TT genotype (CT vs. TT: odds ratio [OR]=0.66; 95% confidence interval [95% CI], 0.45-0.97; and CT/CC vs. TT: OR=0.67; 95% CI, 0.47-0.97, respectively). Combined analysis showed that subjects carrying the miR-34b/c rs4938723 CT/CC and TP53 CG/CC genotypes had a 0.62-fold decreased risk to develop gastric cancer compared with subjects carrying the miR-34b/c rs4938723 TT and TP53 CG/CC genotypes (OR=0.62; 95% CI, 0.40-0.96). These findings suggest that the miR-34b/c rs4938723 may individually and jointly have a protective effect on the risk of gastric risk.
Asunto(s)
MicroARNs/genética , Polimorfismo de Longitud del Fragmento de Restricción , Neoplasias Gástricas/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Growing evidence has indicated that polymorphism present in the miRNA binding site of target gene can alter the ability of miRNAs to bind its target gene and modulate the development and progression of cancer. We aimed to investigate the association between let-7 KRAS rs712 polymorphism and the risk of colorectal cancer (CRC). The let-7 KRAS rs712 was analyzed in a case-control study, including 339 CRC patients and 313 age- and sex-matched controls; the relationship between the polymorphism and the clinicopathological features of CRC was also examined. Individuals carrying the let-7 KRAS rs712 TT genotype and T allele had an increased risk of developing CRC (TT vs. GG, adjusted OR = 2.18; 95% CI, 1.00-4.77; T vs. G, adjusted OR = 1.50; 95% CI, 1.15-1.96). Stratified analyses revealed that CRC patients with the let-7 KRAS rs712 TT genotype were more likely to have clinical stage III or IV disease (OR = 3.29, 95% CI, 1.32-8.20) and distant metastasis (OR = 4.70, 95% CI, 1.81-12.25). These findings provide evidence that the let-7 KRAS rs712 polymorphism may play crucial roles in the etiology of CRC.
Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Anciano , Alelos , Estudios de Casos y Controles , Neoplasias Colorrectales/patología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Oportunidad Relativa , Proteínas Proto-Oncogénicas p21(ras) , Riesgo , Carga TumoralRESUMEN
Nasopharyngeal carcinoma (NPC) is characterized by its highly invasive and metastatic features. Therefore, screening genetic biomarkers of NPC to achieve early diagnose would be of great value for NPC therapy. Single nucleotide polymorphisms in let-7 miRNA binding site in 3' untranslated region of KRAS mRNA have been found to be associated with various cancer risks. In this study, we genotyped the frequency of KRAS rs712 to test its effect on NPC risk in a hospital-based case-control study in a Chinese population, with 188 histologically confirmed NPC patients and 356 cancer-free controls, using polymerase chain reaction-restriction fragment length polymorphism assay. There was no significant difference in the genotype and allele frequencies of the rs712 polymorphism between the NPC patients and the control group (GT vs. GG, OR 0.83, 95% CI 0.57-1.21; TT vs. GG, OR 1.27, 95% CI 0.58-2.75). Our data suggest that the KRAS rs712 polymorphism in let-7 miRNA binding site has no association with NPC risk. Further experiments with larger sample size or other polymorphism sites are needed to verify the result, especially in different ethnic groups.
Asunto(s)
MicroARNs/genética , Neoplasias Nasofaríngeas/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Regiones no Traducidas 3' , Adulto , Pueblo Asiatico/genética , Sitios de Unión , Carcinoma , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Proteínas ras/metabolismoRESUMEN
Matrix Metalloproteinases (MMPs) play an important role in gastric cancer (GC). Accumulated evidence suggests that functional MMP-1 and MMP-7 gene polymorphisms are associated with several tumors. The aim of this study was to investigate two single nucleotide polymorphisms, MMP-1 -1607 1G/2G and MMP-7 -181 A/G, and their potential relationship with GC. We examined 246 GC patients and 252 age-and sex-matched controls from Sichuan province in China. Genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism strategy and DNA sequencing. We also performed a meta-analysis of relevant studies, involving 1084 cases and 1721 controls, to place our findings in a broader context. No significant relationship was observed between the MMP-1 -1607 1G/2G alleles and genotypes and the risk of GC. There were significant differences in the genotypes and allele distributions of the -181 A/G polymorphism of the MMP-7 gene between cases and controls. The -181 A allele carriers had a significantly increased risk of GC compared with -181 G allele carriers (OR=3.051, 95% CI, 1.475-6.310, P=0.002), and the AA genotype of -181 A/G was associated with an increased risk of GC compared with the AG genotype (OR=3.189, 95% CI, 1.523-6.676, P=0.001). A meta-analysis of six studies also showed a significant risk of GC associated with MMP-7 polymorphism.
Asunto(s)
Predisposición Genética a la Enfermedad , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 7 de la Matriz/genética , Polimorfismo de Nucleótido Simple , Neoplasias Gástricas/genética , Adulto , Anciano , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/enzimologíaRESUMEN
Recently, single nucleotide polymorphisms in let-7 miRNA binding site in 3' untranslated region (UTR) of KRAS mRNA have been found to be associated with the cancer risk. In this study, we genotyped the frequency of KRAS rs712 to test its effect on gastric cancer (GC) risk in a hospital-based case-control study in a Chinese population, with 181 histologically confirmed GC patients and 674 cancer-free controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The TT genotype of rs712 was associated with an increased risk of GC when taking GG genotype as a reference (adjusted odds ratio (OR) = 3.05, 95 % confidence interval (CI), 1.53-6.08). Similarly, the T allele of rs712 was associated with a statistically significant increase in susceptibility compared with G allele (adjusted OR = 1.44, 95 % CI, 1.10-1.90). Our data demonstrated that the T allele of the let-7 binding site polymorphism rs712 in KRAS 3' UTR was associated with a significantly increased risk of GC, suggesting that the KRAS rs712 polymorphism may be a genetic marker for the development of GC.
Asunto(s)
MicroARNs/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Neoplasias Gástricas/genética , Proteínas ras/genética , Regiones no Traducidas 3' , Adulto , Anciano , Sitios de Unión , Estudios de Casos y Controles , China , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas p21(ras) , Factores de RiesgoRESUMEN
Basigin may be involved in cardiovascular disease. In our previous study, suppression subtractive hybridization results indicated that basigin may be associated with the early phase of acute myocardial ischemia (AMI) within 1 h. However, little is known regarding the expression of basigin in the early phase of AMI. The aim of the present study was to evaluate the temporal and spatial expression patterns of basigin mRNA and protein levels in AMI in rats. We constructed an AMI model in rats that received left anterior descending coronary artery ligation for 0, 15, 30, 60, 120 or 240 min. Realtime quantitative PCR and in situ hybridization (ISH) were conducted to reveal the basigin mRNA levels in the early ischemic myocardium (EIM) and nonischemic myocardium (NIM). The expression levels of basigin protein were detected using western blot analysis and immunohistochemistry. The expression levels of basigin mRNA and protein significantly changed in the EIM as early as 30 min from ischemia, and the changes continued to be present throughout the ischemic period (P<0.05). The expression levels of basigin mRNA were significantly reduced, whilst those of the protein underwent a significant ~2-fold increase in the EIM. However, there were no significant differences in the basigin mRNA or protein expression levels from 0240 min in the NIM (P>0.05). We failed to detect a signal for basigin mRNA in the myocardium by ISH. Our findings indicated that basigin may be involved in acute myocardial ischemia following continual ischemia for >30 min.
Asunto(s)
Basigina/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Enfermedad Aguda , Animales , Basigina/genética , Western Blotting , Encéfalo/metabolismo , Encéfalo/patología , Regulación de la Expresión Génica , Inmunohistoquímica , Hibridación in Situ , Masculino , Miocardio/metabolismo , Miocardio/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVE: To investigate the expression of Sjögren's syndrome antigen B (SSB) gene and SSB protein in the early ischemic myocardium in rats. METHODS: Adult healthy Sprague-Dawley rats were randomly divided into groups of operation [myocardial ischemia (MI) and non-ischemia (NI)], non-operation (NO) and sham-operation (SO) (n = 6 for MI and NI; n = 4 for NO and SO). According to time of ischemia, it was then divided into groups of 0 min, 15 min, 30 min, 60 min, 120 min, and 240 min. The expression of SSB gene in the myocardium was examined by real-time PCR, and the expression of SSB protein was examined by Western blot and immunofluorescence staining. RESULTS: The expressions of SSB gene was down-regulated at early stage of ischemia. There was significant difference between 0 min and 120 min at the level of expression of SSB gene in MI group, so did that between 120 min group and NO group (P < 0.05). The expression of SSB protein at 60 min after ischemia was significantly decreased compared with that in the group of 0 min (P < 0.05). The expression of SSB protein in NI groups was significantly higher than that in MI groups at the time of 60 min and 120 min after myocardial ischemia (P < 0.05). Additionally, the expression of SSB protein was mainly located in the myocardial nucleus, myocardial plasma, and plasma membrane of partial myocardiocytes according to the result of immunofluorescence staining. CONCLUSION: SSB may participate in pathophysiologic regulation process in myocardial cells at the early stage of myocardial ischemia in rats.
Asunto(s)
Autoantígenos/metabolismo , Isquemia Miocárdica/genética , Miocardio/metabolismo , Ribonucleoproteínas/metabolismo , Animales , Autoantígenos/genética , Masculino , Isquemia Miocárdica/metabolismo , Ratas , Ratas Sprague-Dawley , Ribonucleoproteínas/genética , Factores de Tiempo , Antígeno SS-BRESUMEN
The miR-34 family members, described as potential tumor suppressors, were downregulated in colorectal cancer (CRC). Loss of miR-34 impairs TP53-mediated cell death, while overexpression of miR-34 induces apoptosis. A potentially functional polymorphism (i.e., rs4938723T/C) in the promoter region of pri-miR-34b/c was predicted to influence the GATA-X binding sites. We aimed to investigate the association between miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms and the risk of CRC. We genotyped the two polymorphisms in 347 CRC patients and 488 healthy controls using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing assay. We found that the CC genotype and C allele of the miR-34b/c rs4938723 were associated with a significantly decreased risk of CRC compared with the TT genotype and T allele (CC vs. TT: adjusted OR=0.56; 95% CI, 0.34-0.91; C vs. T: adjusted OR=0.78; 95% CI, 0.64-0.97). In combined analysis, a borderline significance was also observed in subjects carrying the rs4938723 CT/CC and TP53 GG genotypes (adjusted OR=0.66; 95% CI, 0.43-0.99). These findings indicate that the rs4938723 in the promoter region of pri-miR-34b/c was a protective factor for the development of CRC. As the significance is marginal, further replication studies are warranted to confirm these results.
Asunto(s)
Neoplasias Colorrectales/genética , Variación Genética , MicroARNs/genética , Regiones Promotoras Genéticas/genética , Neoplasias Colorrectales/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Several lines of evidence indicate that inflammatory processes play pivotal role in the development of intracranial aneurysm (IA). Recently, polymorphisms in the interleukin-12 (IL-12) gene were shown to be associated with immune-mediated inflammatory disease. The aim of this study was to investigate the interactions of IL-12A and IL-12B polymorphisms on the risk of IA in a Chinese population. A total of 422 individuals (including 164 patients with IA and 258 controls) were involved in the study. The polymorphisms (i.e., rs2243115 and rs568408 in IL-12A and rs3212227 in IL-12B) were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay and DNA sequencing. We found an association of the AC/CC genotypes and C allele of IL-12B rs3212227 with an increased risk of IA, compared with the AA genotype and A allele (AC/CC vs. AA: OR = 2.09, 95 % CI: 1.29-3.38; C vs. A: OR = 1.45, 95 % CI: 1.10-1.91). Moreover, a significant gene interaction of IL-12A and IL-12B was evident on the risk of IA, and subjects carrying variant genotypes of IL-12B rs3212227 had an increased risk of IA. In the stratified analysis by gender, the IL-12B rs3212227 AC/CC genotypes had an increased risk of IA compared with the AA genotype in male patients (AC/CC vs. AA: OR = 4.63, 95 % CI: 1.92-11.16). These findings suggest that the IL-12A and IL-12B independently and jointly be involved in the susceptibility to IA.
Asunto(s)
Predisposición Genética a la Enfermedad , Subunidad p35 de la Interleucina-12/genética , Subunidad p40 de la Interleucina-12/genética , Aneurisma Intracraneal/genética , Polimorfismo de Nucleótido Simple/genética , Estudios de Casos y Controles , Demografía , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVES: The purpose of this study was to evaluate the effects of interleukin-13 (IL-13) polymorphisms on the risk of asthma using a meta-analysis. DESIGN AND METHODS: Fifteen publications were identified by searching Pubmed, Embase, ISI, OVID, and EBSCO databases. Odds ratios with corresponding 95% confidence intervals were computed to estimate the association between IL-13 polymorphisms and risk of asthma. RESULTS: The polymorphisms of R130Q (rs20541) and -1112C/T (rs1800925) in IL-13 gene were associated with significantly increased risks of asthma in overall analyses. Subgroup analyses showed that the elevated risks occurred in adult-onset asthma, Caucasians, and high quality studies. CONCLUSIONS: This meta-analysis provides evidence that the R130Q and -1112C/T polymorphisms in IL-13 are risk factors for asthma.
Asunto(s)
Asma/genética , Interleucina-13/genética , Polimorfismo de Nucleótido Simple , Adulto , Edad de Inicio , Sustitución de Aminoácidos , Niño , Estudios de Asociación Genética , Humanos , Regiones Promotoras Genéticas , Factores de Riesgo , Población BlancaRESUMEN
MicroRNAs are noncoding RNA molecules of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. The aim of this study was to investigate whether pri-miR-218 rs11134527 A/G polymorphism influences the risk of hepatocellular carcinoma (HCC) or not. pri-miR-218 rs11134527 A/G was genotyped in 302 HCC patients and 513 control subjects using the polymerase chain reaction-restriction fragment length polymorphism assay. The AG genotype of pri-miR-218 rs11134527 A/G was associated with family history (p=0.018, odds ratio [OR]=2.96, 95% confidence interval [CI]: 1.16-7.56) and elevated serum α-fetoprotein (serum alpha-fetoprotein [AFP]) levels (≥20 ng/mL; p=0.009, OR=1.92, 95% CI: 1.17-3.14) in HCC patients. These findings suggested that the AG genotype of pri-miR-218 rs11134527 might relate to genetic predisposition and be involved in regulating the expression of AFP in Chinese HCC patients.
Asunto(s)
Pueblo Asiatico/genética , Carcinoma Hepatocelular/genética , Predisposición Genética a la Enfermedad , Neoplasias Hepáticas/genética , MicroARNs/genética , Polimorfismo Genético/genética , Adulto , Carcinoma Hepatocelular/epidemiología , Estudios de Casos y Controles , China/epidemiología , ADN/genética , Femenino , Genotipo , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de Riesgo , alfa-Fetoproteínas/genéticaRESUMEN
Emerging evidence has shown that angiotensin I-converting enzyme (ACE) plays pivotal roles not only in the regulation of cardiovascular homeostasis but also in the process of tumorigenesis. A common ACE I/D polymorphism has been found to be functional, with the D allele displaying a higher plasma ACE level and ACE activity. The purpose of this study was to investigate whether the ACE I/D polymorphism was related to the risk of nasopharyngeal carcinoma (NPC). The study included 175 patients with NPC and 279 age- and sex-matched control subjects. The ACE I/D polymorphism was identified by a polymerase chain reaction analysis. No association was found between the ACE I/D polymorphism and risk of NPC (ID vs. II: odds ratio [OR] = 0.77, 95% confidence interval [CI] 0.51-1.17; DD vs. II: OR = 0.98, 95%CI 0.56-1.72, respectively). This finding indicates that the ACE I/D polymorphism may not play a role in susceptibility to NPC. Further studies are warranted to confirm this finding, especially in ethnically disparate populations.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Neoplasias Nasofaríngeas/enzimología , Neoplasias Nasofaríngeas/genética , Peptidil-Dipeptidasa A/genética , Adulto , Carcinoma , Estudios de Casos y Controles , Femenino , Humanos , Mutación INDEL/genética , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Polimorfismo Genético , Factores de RiesgoRESUMEN
DNA mismatch repair, known as a fundamentally biological pathway, plays key roles in maintaining genomic stability, eliminating mismatch bases and preventing both mutagenesis in the short term and cancerogenesis in the long term. Polymorphisms of MLH1 in individuals may have an effect on the DNA repair capacity and therefore on cancer risk. Recently, emerging studies have been done to evaluate the association between MLH1 -93 G/A polymorphism and cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. In this meta-analysis, we assessed reported studies of association between the MLH1 -93 G/A polymorphism and cancer risk including 13 691 cancer cases and 14 068 controls from 17 published studies. A borderline significant association between the MLH1 -93 G/A polymorphism and cancer risk was observed in overall analysis [heterozygote: odds ratio (OR) = 1.15; 95% confidence interval (CI) 1.05-1.26; homozygote: OR = 1.21; 95% CI, 1.04-1.40; dominant model: OR = 1.13; 95% CI 1.01-1.26; recessive model: OR = 1.21; 95% CI 1.07-1.35, respectively]. In subgroup analysis by ethnicity, significantly increased risks were found in Asian population and mixed population but not in Caucasian population. After stratified analysis according to the quality of literature, increased cancer risks were observed in the studies of lower quality but not in the studies of higher quality. Similarly, elevated cancer risks were observed in hospital-based studies but not in population-based studies. These findings showed no persuasive evidence that MLH1 -93 G/A polymorphism was associated with an increased risk of cancer. On the conservative standpoint, well-designed population-based studies with larger sample size in different ethnic groups should be performed to further confirm these results.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Reparación de la Incompatibilidad de ADN , Predisposición Genética a la Enfermedad , Neoplasias/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Frecuencia de los Genes , Heterogeneidad Genética , Humanos , Homólogo 1 de la Proteína MutL , Sesgo de Publicación , RiesgoRESUMEN
BACKGROUND AND OBJECTIVES: Glutathione S-transferases (GSTs) are multifunctional enzymes that play a key role in the detoxification of varieties of both endogenous products of oxidative stress and exogenous carcinogens. METHODS: In this meta-analysis, twenty-five studies were identified by searching PubMed, EMBASE, ISI Web of Science and CBM databases: 23 evaluated GSTM1 and 19 evaluated GSTT1. Crude odds ratios with corresponding 95% confidence intervals were used to estimate the association between GSTM1 and GSTT1 polymorphisms and risk of cervical neoplasia. Subgroup analyses were conducted by pathological history, ethnicity, source of DNA for genotyping, quality score, and matching variable. RESULTS: The null genotypes of GSTM1 and GSTT1 polymorphisms were associated with a significantly increased risk of cervical neoplasia (for GSTM1: OR = 1.40; 95%CI, 1.19-1.65; for GSTT1: OR = 1.30; 95%CI, 1.05-1.62, respectively). Subgroup analyses showed that the null genotype of GSTM1 increased the risk of cervical neoplasia in Asians, studies with DNA isolation from white blood cells and tissue samples, both high and low quality studies, and matched studies. In GSTM1-GSTT1 interaction analysis, individuals with dual null genotype were associated with a significantly increased risk of cervical neoplasia (OR = 1.72; 95%CI, 1.18-2.51). CONCLUSION: These findings indicate that GSTM1 and GSTT1 polymorphisms, particularly GSTM1-GSTT1 interaction, may play critical roles in the development of cervical neoplasia. A conservative manner should be adopted to interpret these results because of obvious heterogeneity between-study, unadjusted data, and relatively small sample size in this meta-analysis. Well designed studies with larger sample size are of great value to confirm these results.
Asunto(s)
Glutatión Transferasa/genética , Neoplasias del Cuello Uterino/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Glutatión Transferasa/metabolismo , Humanos , Oportunidad Relativa , Polimorfismo Genético/genética , Unión Proteica/genética , Unión Proteica/fisiología , Neoplasias del Cuello Uterino/enzimologíaRESUMEN
Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA (miRNA) expression levels or processing and contribute to susceptibility to a wide range of diseases. We investigated the correlation between four SNPs (rs11614913, rs3746444, rs2910164, and rs229283) in pre-miRNAs and the risk of asthma in 220 asthma patients and 540 controls using polymerase chain reaction-restriction fragment length polymorphism methodology and DNA-sequencing. There were significant differences in the genotype and allelic distribution of rs2910164G/C and rs2292832C/T polymorphisms among cases and controls. The CC genotype and C allele of rs2910164G/C were significantly associated with a decreased risk of asthma (CC vs. GG, odds ratio [OR] = 0.51, 95% confidence interval [CI]: 0.31-0.82; C vs. G, OR = 0.74, 95% CI: 0.59-0.93). Similarly, the TT genotype and T allele of rs2292832C/T were significantly associated with a decreased risk of asthma (TT vs. CC, OR = 0.56, 95% CI: 0.33-0.95; T vs. C, OR = 0.71, 95% CI: 0.53-0.95). However, no significant association between the other two polymorphisms (i.e., rs11614913C/T and rs3746444C/T) and the risk of asthma was observed. Our data indicate that rs2910164G/C and rs2292832C/T may play a role in the development of asthma.
Asunto(s)
Pueblo Asiatico/genética , Asma/genética , Predisposición Genética a la Enfermedad/genética , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Humanos , MasculinoRESUMEN
OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airway obstruction and persistent chronic airway inflammation and is influenced by genetic and environmental factors. This study aimed to explore the genetic aspect of its initial occurrence. DESIGN AND METHODS: We conducted a case-control study of 432 COPD patients and 511 control subjects frequency-matched in age and gender distribution. We genotyped three single nucleotide polymorphisms (SNPs) in pre-miRNAs using a PCR-RFLP assay and evaluated their relevance to COPD susceptibility. RESULTS: We found that the TT genotype and T allele of miR-196a2 rs11614913 were significantly associated with a decreased risk for COPD, compared with the CC genotype and C allele. Similarly, the GG genotype and G allele of miR-499 rs3746444 were associated with a decreased risk for COPD, compared with the AA genotype and A allele. CONCLUSIONS: These findings suggest that both rs11614913 and rs3746444 may be involved in susceptibility to COPD.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , MicroARNs/genética , Polimorfismo de Nucleótido Simple/genética , Enfermedad Pulmonar Obstructiva Crónica/genética , Anciano , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Factores de RiesgoRESUMEN
Emerging evidence has shown that miRNAs participate in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphism (SNP) which located in the pre-miRNA may affect the processing and then influence the expression of mature miRNA. Previous studies yielded conflicting results as to the association of two common polymorphisms in pre-miRNAs (i.e. hsa-miR-146 rs2910164 and hsa-miR-196a2 rs11614913) with breast cancer. To derive a more precise effect on the association between these polymorphisms and breast cancer risk, we conducted a meta-analysis. Through retrieving PubMed for the period up to May 2010, a total of four studies were identified with 3,007 cases and 3,718 controls for has-miR-146a rs2910164 polymorphism and with 3,287 cases and 4,298 controls for hsa-miR-196a2 rs11614913 polymorphism. We found that individuals carrying CC genotype of has-miR-196a2 rs11614913 polymorphism was associated with an increased breast cancer risk in homozygote comparison (OR = 1.30; 95% CI, 1.01-1.68), and dominant model (OR = 1.11; 95% CI, 1.01-1.23). However, no significant association between has-miR-146a rs2910164 polymorphism and breast cancer risk was observed in all comparison models tested. These findings suggest that has-miR-196a2 rs11614913 polymorphism may play crucial roles in breast cancer development.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , MicroARNs/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Riesgo , Medición de RiesgoRESUMEN
Growing evidence suggests that RAD51 plays a pivotal role in the repair of DNA double-strand breaks and the maintenance of genomic stability. A single nucleotide polymorphism, 135G/C, has been identified in the 5' untranslated region of the RAD51 gene and has been shown to influence gene transcription activity. Previous studies yielded conflicting results as to the association of 135G/C polymorphism with breast cancer. We aimed to assess the effect of 135G/C of RAD51 on breast cancer susceptibility with the use of a meta-analysis. We performed a meta-analysis of 21 published case-control studies up to April 2010. We found that the CC genotype was associated with a significantly increased risk of breast cancer when compared with the GG, CG, and CG/GG genotypes. Subgroup analyses showed that individuals carrying the CC genotype were associated with an elevated tumor risk in European populations and in sporadic breast cancer. After stratified analyses according to manuscript quality, the CC genotype was associated with a significantly increased risk of breast cancer compared with the CG genotype in studies of both higher and lower quality. However, significantly elevated risk was found in studies of higher quality, but not in studies of lower quality when homozygote and a recessive comparison model were tested. This meta-analysis indicates that RAD51 135G/C polymorphism may be identified as a susceptibility locus for breast cancer.