RESUMEN

Nonsyndromic biliary atresia (BA) is a rare polygenic disease, with autoimmunity, virus infection and inflammation thought to play roles in its pathogenesis. We conducted a genome-wide association study in 336 nonsyndromic BA infants and 8900 controls. Our results validated the association of rs17095355 in ADD3 with BA risk (odds ratio (OR) = 1.70, 95% confidence interval (95% CI) = 1.49-1.99; p = 4.07 × 10-11). An eQTL analysis revealed that the risk allele of rs17095355 was associated with increased expression of ADD3. Single-cell RNA-sequencing data and immunofluorescence analysis revealed that ADD3 was moderately expressed in cholangiocytes and weakly expressed in hepatocytes. Immuno-fluorescent staining showed abnormal deposition of ADD3 in the cytoplasm of BA hepatocytes. No ADD3 auto-antibody was observed in the plasma of BA infants. In the HLA gene region, no variants achieved genome-wide significance. HLA-DQB1 residue Ala57 is the most significant residue in the MHC region (OR = 1.44, 95% CI = 1.20-1.74; p = 1.23 × 10-4), and HLA-DQB1 was aberrantly expressed in the bile duct cells. GWAS stratified by cytomegalovirus (CMV) IgM status in 87 CMV IgM (+) BA cases versus 141 CMV IgM (-) BA cases did not yield genome-wide significant associations. These findings support the notion that common variants of ADD3 account for BA risk. The HLA genes might have a minimal role in the genetic predisposition of BA due to the weak association signal. CMV IgM (+) BA patients might not have different genetic risk factor profiles compared to CMV IgM (-) subtype.

Asunto(s)

Atresia Biliar , Infecciones por Citomegalovirus , Antígenos HLA , Humanos , Lactante , Atresia Biliar/complicaciones , Atresia Biliar/genética , Atresia Biliar/patología , Proteínas de Unión a Calmodulina/metabolismo , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/inmunología , Pueblos del Este de Asia , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Inmunoglobulina M/metabolismo , Antígenos HLA/genética

RESUMEN

IMPORTANCE: Multiple studies indicate a possible correlation between ADD3 rs2501577 and biliary atresia susceptibility; however, a conclusive determination has yet to be made. OBJECTIVE: Investigate the role of ADD3 rs2501577 in biliary atresia susceptibility across diverse populations. DATA SOURCES: The study protocol has been registered on PROSPERO, an international platform for systematic review registration (PROSPERO ID: CRD42023384641). The following databases will be searched until February 1, 2023: PubMed, Embase, Cochrane, CBM, Web of Science, and CNKI. STUDY SELECTION: Eight studies were selected from seven papers to assess the data. A total of 7651 participants were included, consisting of 1662 in the BA group and 5989 in the NC group. DATA EXTRACTION AND SYNTHESIS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed while conducting the systematic reviews and meta-analyses. Two authors independently assessed the quality of the included studies using the Newcastle-Ottawa Quality Assessment Scale. The significance of the pooled odds ratio (OR) was evaluated with a Z test, and statistical heterogeneity across studies was assessed using the I2 and Q statistics. Publication bias was assessed using Egger's and Begg's tests. MAIN OUTCOME(S) AND MEASURE(S): The primary study outcome was the development of biliary atresia. Subgroup analysis was performed based on race, region, and assessment of Hardy-Weinberg equilibrium (HWE). RESULTS: The studies indicate that the ADD3 rs2501577 susceptibility locus increases the risk of developing biliary atresia, regardless of allelic, homozygote, dominant, and recessive gene inheritance models. Furthermore, ADD3 has been found to be associated with apoptosis, cell cycle, and cell damage repair based on functional analysis. CONCLUSIONS AND RELEVANCE: The ADD3 rs2501577 polymorphic locus is associated with an increased risk of biliary atresia, particularly in Asian populations. This study recommends further investigation of the ADD3 rs2501577 locus in Asian populations to validate its role in the diagnosis of biliary atresia.

Asunto(s)

Atresia Biliar , Humanos , Atresia Biliar/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas de Unión a Calmodulina/genética , Oportunidad Relativa

RESUMEN

Cerebral palsy (CP) causes neurological disability in early childhood. Hypoxic-ischaemic injury plays a major role in its aetiology, nevertheless, genetic and epigenetic factors may contribute to the clinical presentation. Mutations in ADD3 (encoding γ-adducin) gene have been described in a monogenic form of spastic quadriplegic cerebral palsy (OMIM 601568). We studied a 16-year-old male with spastic diplegia. Several investigations including neurometabolic testing, brain and spine magnetic resonance imaging (MRI) and CGH-Array were normal. Further, clinical genetics assessment and whole exome sequencing (WES) gave the diagnosis. We generated an animal model using Drosophila to study the effects of γ-adducin loss and gain of function. WES revealed a biallelic variant in the ADD3 gene, NM_016824.5(ADD3): c.1100G > A, p.(Gly367Asp). Mutations in this gene have been described as an ultra-rare autosomal recessive, which is a known form of inherited cerebral palsy. Molecular modelling suggests that this mutation leads to a loss of structural integrity of γ-adducin and is therefore expected to result in a decreased level of functional protein. Pan-neuronal over-expression or knock-down of the Drosophila ortholog of ADD3 called hts caused a reduction of life span and impaired locomotion thereby phenocopying aspects of the human disease. Our animal experiments present a starting point to understand the biological processes underpinning the clinical phenotype and pathogenic mechanisms, to gain insights into potential future methods for treating or preventing ADD3 related spastic quadriplegic cerebral palsy.

Asunto(s)

Parálisis Cerebral , Paraparesia Espástica , Paraplejía Espástica Hereditaria , Animales , Masculino , Preescolar , Humanos , Adolescente , Drosophila/genética , Paraparesia Espástica/genética , Espasticidad Muscular , Mutación , Paraplejía Espástica Hereditaria/genética , Proteínas de Unión a Calmodulina/genética

RESUMEN

Biliary atresia (BA) is a devastating liver disease in neonates. Liver fibrosis is regarded as a universal and prominent feature of BA. Studies have revealed that long non-coding RNAs (lncRNAs) regulate cellular processes during the development of liver fibrosis in BA. Long non-coding RNA-adducin 3 antisense RNA1 (lnc-ADD3-AS1) has been shown to increase susceptibility to BA. However, the role of lnc-ADD3-AS1 in liver fibrosis in BA remains unclear. Here, we investigated the role of lnc-ADD3-AS1 in the proliferation, migration, and apoptosis of the immortalized human hepatic stellate cell (HSC) line, LX-2. We successfully overexpressed and silenced lnc-ADD3-AS1 in LX-2 cells using adenovirus vectors and evaluated the proliferation of transfected cells using the Cell Counting Kit-8 (CCK8) assay. Cell apoptosis was detected using annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining and flow cytometry. We then analyzed cell migration by performing wound-scratch and transwell migration assays. Our results show that lnc-ADD3-AS1 significantly promoted LX-2 cell proliferation and attenuated apoptosis. More importantly, lncRNA-ADD3-AS1 significantly accelerated the migration of LX-2 cells. Our data indicated that lncRNA-ADD3-AS1 plays a role in the pathogenesis of liver fibrosis in patients with BA and may serve as a potential diagnostic marker for monitoring liver fibrosis in BA or as a therapeutic target for the disease.

Asunto(s)

Atresia Biliar , ARN Largo no Codificante , Atresia Biliar/genética , Proteínas de Unión a Calmodulina , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , Recién Nacido , Cirrosis Hepática/genética , ARN sin Sentido/metabolismo , ARN Bacteriano , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo

RESUMEN

OBJECTIVE: The expression of cytoskeleton-related protein γ-adducin (ADD3) was abnormally reduced in some tumors. Functional experiments demonstrated that it could inhibit the malignant progression of lung cancer and glioma, whereas the involvement of ADD3 in osteosarcoma was not clear. This study aimed to investigate the role of ADD3 in osteosarcoma and its upstream regulatory mechanisms. METHODS: ADD3 was knocked down by siRNA transfection and the expression level of ADD3 was determined using quantitative real-time PCR assay and Western blot. CCK-8 assay and colony formation were performed to detect the capacity of cell proliferation. Transwell assay and PI and Annexin V-FITC staining were used to determine cell migration and apoptosis, respectively. Luciferase reporter experiment was performed to investigate the interaction between ADD3 and miR-23b-3p. RESULTS: Based on gene silencing assays, we showed that knockdown of ADD3 suppressed apoptosis and promoted the proliferation and migration of osteosarcoma cells, revealing inhibitory effects of ADD3 in osteosarcoma. Luciferase reporter gene assays confirmed that miR-23b-3p could bind to the 3'-UTR of ADD3. Upregulation of miR-23b-3p not only inhibited the expression of ADD3, but also released the tumor suppressive role of ADD3 on the proliferation and migration of osteosarcoma cells. CONCLUSIONS: Our study found that ADD3 functioned as a tumor suppressor gene during osteosarcoma development. The abnormal upregulation of miR-23b-3p targeted the expression of ADD3 and resulted in accelerated osteosarcoma cell proliferation and migration. Thus, the miR-23b-3p/ADD3 axis contributes to the development of osteosarcoma and ADD3 is a key driver of malignancy.

Asunto(s)

Neoplasias Óseas , Proteínas de Unión a Calmodulina , MicroARNs , Osteosarcoma , Humanos , Regiones no Traducidas 3' , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Proteínas de Unión a Calmodulina/genética , Línea Celular Tumoral , Proliferación Celular/genética , MicroARNs/genética , Osteosarcoma/genética , Osteosarcoma/patología

RESUMEN

Loss of heterozygosity (LOH) on chromosome 10 frequently occurs in gliomas. Whereas genetic loci with allelic deletion often implicate tumor suppressor genes, a putative tumor suppressor Adducin3 (ADD3) mapped to chromosome 10q25.2 was found to be preferentially downregulated in high-grade gliomas compared with low-grade lesions. In this study, we unveil how the assessment of ADD3 deletion provides clinical significance in glioblastoma (GBM). By deletion mapping, we assessed the frequency of LOH in forty-three glioma specimens using five microsatellite markers spanning chromosome 10q23-10qter. Data were validated in The Cancer Genome Atlas (TCGA) cohort with 203 GBM patients. We found that allelic loss in both D10S173 (ADD3/MXI1 locus) and D10S1137 (MGMT locus) were positively associated with tumor grading and proliferative index (MIB-1). However, LOH events at only the ADD3/MXI1 locus provided prognostic significance with a marked reduction in patient survival and appeared to have diagnostic potential in differentiating high-grade gliomas from low-grade ones. Furthermore, we showed progressive loss of ADD3 in six out of seven patient-paired gliomas with malignant progression, as well as in recurrent GBMs. These findings suggest the significance of ADD3/MXI1 locus as a promising marker that can be used to refine the LOH10q assessment. Data further suggest the role of ADD3 as a novel tumor suppressor, whereby the loss of ADD3 is indicative of a progressive disease that may at least partially account for rapid disease progression in GBM. This study revealed for the first time the downregulation of ADD3 on the genetic level resulting from copy number deletion.

RESUMEN

Accumulating evidence indicates that the alternative splicing program undergoes extensive changes during cancer development and progression. The RNA-binding protein QKI-5 is frequently downregulated and exhibits anti-tumor activity in lung cancer. Howeve-r, little is known about the functional targets and regulatory mechanism of QKI-5. Here, we report that upregulation of exon 14 inclusion of cytoskeletal gene Adducin 3 (ADD3) significantly correlates with a poor prognosis in lung cancer. QKI-5 inhibits cell proliferation and migration in part through suppressing the splicing of ADD3 exon 14. Through genome-wide mapping of QKI-5 binding sites in vivo at nucleotide resolution by iCLIP-seq analysis, we found that QKI-5 regulates alternative splicing of its target mRNAs in a binding position-dependent manner. By binding to multiple sites in an upstream intron region, QKI-5 represses the splicing of ADD3 exon 14. We also identified several QKI mutations in tumors, which cause dysregulation of the splicing of QKI targets ADD3 and NUMB. Taken together, our results reveal that QKI-mediated alternative splicing of ADD3 is a key lung cancer-associated splicing event, which underlies in part the tumor suppressor function of QKI.

Asunto(s)

Empalme Alternativo/genética , Proteínas de Unión a Calmodulina/genética , Citoesqueleto/genética , Neoplasias Pulmonares/genética , Proteínas de Unión al ARN/genética , Células A549 , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo/genética , Exones/genética , Genes Supresores de Tumor/fisiología , Células HEK293 , Humanos , Intrones/genética , Neoplasias Pulmonares/patología , ARN Mensajero/genética , Regulación hacia Arriba/genética

RESUMEN

Glioblastoma multiforme (GB) is one of the most aggressive tumors. Despite continuous efforts to improve its clinical management, there is still no strategy to avoid a rapid and fatal outcome. EGFR amplification is the most characteristic alteration of these tumors. Although effective therapy against it has not yet been found in GB, it may be central to classifying patients. We investigated somatic-copy number alterations (SCNA) by multiplex ligation-dependent probe amplification in a series of 137 GB, together with the detection of EGFRvIII and FISH analysis for EGFR amplification. Publicly available data from 604 patients were used as a validation cohort. We found statistical associations between EGFR amplification and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3. Interestingly, we found that both EGFRvIII and losses on ADD3 were independent markers of bad prognosis (p = 0.028 and 0.014, respectively). Finally, we got an unsupervised hierarchical classification that differentiated three clusters of patients based on their genetic alterations. It offered a landscape of EGFR co-alterations that may improve the comprehension of the mechanisms underlying GB aggressiveness. Our findings can help in defining different genetic profiles, which is necessary to develop new and different approaches in the management of our patients.

Asunto(s)

Neoplasias Encefálicas/genética , Proteínas de Unión a Calmodulina/metabolismo , Glioblastoma/genética , Familia de Multigenes , Neoplasias Encefálicas/patología , Variaciones en el Número de Copia de ADN/genética , Receptores ErbB/metabolismo , Femenino , Amplificación de Genes , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Transducción de Señal/genética , Análisis de Supervivencia

RESUMEN

Biliary atresia (BA) is an idiopathic neonatal cholestatic disease. Recent genome-wide association study (GWAS) revealed that common variation of ADD3, GPC1, ARF6, and EFEMP1 gene was associated with BA susceptibility. We aimed to evaluate the association of these genes with BA in Chinese population. Twenty single nucleotide polymorphisms (SNPs) in these four genes were genotyped in 340 BA patients and 1,665 controls. Three SNPs in ADD3 were significantly associated with BA, and rs17095355 was the top SNP (PAllele = 3.23×10-6). Meta-analysis of published data and current data indicated that rs17095355 was associated with BA susceptibility in Asians and Caucasians. Three associated SNPs were expression quantitative trait loci (eQTL) for ADD3. Two GPC1 SNPs in high linkage disequilibrium (LD) showed nominal association with BA susceptibility (PAllele = 0.03 for rs6707262 and PAllele = 0.04 for rs6750380), and were eQTL of GPC1. Haplotype harboring these two SNPs almost reached the study-wide significance (P = 0.0035). No association for ARF6 and EFEMP1 was found with BA risk in the current population. Our study validated associations of ADD3 and GPC1 SNPs with BA risk in Chinese population and provided evidence of epistatic contributions of genetic factors to BA susceptibility.

Asunto(s)

Atresia Biliar/genética , Proteínas de Unión a Calmodulina/genética , ADN/genética , Glipicanos/genética , Polimorfismo de Nucleótido Simple , Atresia Biliar/metabolismo , Proteínas de Unión a Calmodulina/metabolismo , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Glipicanos/metabolismo , Humanos , Lactante , Masculino , Sitios de Carácter Cuantitativo

RESUMEN

BACKGROUND: The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ-adducin (ADD3), a cytoskeletal protein encoded by Add3. METHODS: We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats. RESULTS: This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats-a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BKα and BK channel current. FHH and Add3 knockout rats exhibited impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension. CONCLUSIONS: This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.

Asunto(s)

Proteínas de Unión a Calmodulina/genética , Hipertensión/complicaciones , Enfermedades Renales/etiología , Mutación/efectos de los fármacos , Circulación Renal/genética , Animales , Modelos Animales de Enfermedad , Homeostasis , Hipertensión/genética , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Músculo Liso Vascular/fisiología , Miocitos del Músculo Liso/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas

RESUMEN

Emerging evidence suggests that circular RNA (circRNA) plays a fundamental role in tumorigenesis. However, its contribution to hepatocellular carcinoma (HCC) malignancy remains largely unknown. Here, we performed circRNA microarray expression profile in four paired HCC and normal tissues, and found that circ-ADD3, a novel circRNA derived from linear ADD3 exon 4 to exon 12, was significantly downregulated in HCC, which was further validated in 112 matched HCC and paracancerous tissues. High circ-ADD3 expression was negatively correlated with vascular invasion, intrahepatic metastasis as well as distant metastasis. Moreover, it was identified as an effective biomarker for diagnosis and prognosis of HCC. Functionally, exogenous expression of circ-ADD3 dramatically weakened HCC cell invasion and metastasis both in vitro and in vivo. Mechanistically, circ-ADD3 was capable of reinforcing the interaction between CDK1 and EZH2, resulting in increased EZH2 ubiquitination and subsequent degradation via phosphorylation at Thr-345 and Thr-487 sites. The decreased EZH2 markedly increased the expression of a cohort of anti-metastatic genes, including circ-ADD3, by reducing H3K27me3 levels on their promoter regions, which formed a regulatory circuit, thereby dampening HCC metastasis. Taken together, our findings unveil the essential role of circ-ADD3 in inhibiting HCC metastasis through regulation of EZH2 stability.

RESUMEN

BACKGROUND: Weighted co-expression network analysis (WGCNA) is a powerful systems biology method to describe the correlation of gene expression based on the microarray database, which can be used to facilitate the discovery of therapeutic targets or candidate biomarkers in diseases. OBJECTIVE: To explore the key genes in the development of Alzheimer's disease (AD) by using WGCNA. METHODS: The whole gene expression data GSE1297 from AD and control human hippocampus was obtained from the GEO database in NCBI. Co-expressed genes were clustered into different modules. Modules of interest were identified through calculating the correlation coefficient between the module and phenotypic traits. GO and pathway enrichment analyses were conducted, and the central players (key hub genes) within the modules of interest were identified through network analysis. The expression of the identified key genes was confirmed in AD transgenic mice through using qRT-PCR. RESULTS: Two modules were found to be associated with AD clinical severity, which functioning mainly in mineral absorption, NF-κB signaling, and cGMP-PKG signaling pathways. Through analysis of the two modules, we found that metallothionein (MT), Notch2, MSX1, ADD3, and RAB31 were highly correlated with AD phenotype. Increase in expression of these genes was confirmed in aged AD transgenic mice. CONCLUSION: WGCNA analysis can be used to analyze and predict the key genes in AD. MT1, MT2, MSX1, NOTCH2, ADD3, and RAB31 are identified to be the most relevant genes, which may be potential targets for AD therapy.

Asunto(s)

Enfermedad de Alzheimer/genética , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad/genética , Proteínas de Unión a Calmodulina/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Factor de Transcripción MSX1/genética , Masculino , Escala del Estado Mental , Metalotioneína/genética , ARN Mensajero/metabolismo , Receptor Notch2/genética , Biología de Sistemas , Proteínas de Unión al GTP rab/genética

RESUMEN

Biliary atresia (BA) is a multifactorial pathogenic disease with possible genetic components. As a member of membrane skeletal proteins in the liver and bile ducts, a haplotype composed by five single nucleotide polymorphisms (SNPs) on adducin 3 (ADD3) has been identified as associated with BA. However, limited study was designed to further elaborate the mutual relationship amongst those replicated SNPs to disease. We selected three susceptibility SNPs in ADD3 and conducted a replication study using 510 BA cases and 1473 controls to evaluate the individual function of the SNPs and further stratified the potential roles with disease and its subclinical features. Two SNPs in ADD3 were replicated as associated with BA (1.60E-04 ≤ P≤1.70E-04, 1.33 ≤ odds ratio (OR) ≤ 1.58 for rs17095355, 2.10E-04 ≤ P≤5.30E-04, 1.26 ≤ OR ≤ 1.57 for rs2501577). Though we failed to replicate the individual association of rs10509906 to disease, the intragenic epistatic effect between rs10509906 and rs2501577 was suggested as exhibiting susceptibility to BA, further cross-validated by multifactor dimensionality reduction (MDR) (P=0.068, OR = 1.37), which may explain extra hidden heritability of ADD3 to BA. Furthermore, through subclinical stratification, we also observed the association of risk to disease mainly came from the female patients.

Asunto(s)

Atresia Biliar/genética , Proteínas de Unión a Calmodulina/genética , Epistasis Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Aminopeptidasas/genética , Pueblo Asiatico , Atresia Biliar/diagnóstico , Atresia Biliar/etnología , Atresia Biliar/patología , Estudios de Casos y Controles , Femenino , Expresión Génica , Haplotipos , Humanos , Masculino , Reducción de Dimensionalidad Multifactorial , Oportunidad Relativa , Factores de Riesgo , Factores Sexuales

RESUMEN

BACKGROUND: A genome-wide association study in East Asians suggested a genetic association between biliary atresia (BA) and a cluster of variants within the Adducin 3 (ADD3) and ADD3 antisense RNA1 (ADD3-AS1) genes. Another study in Thai neonates reported an association between BA and rs17095355. To validate those findings, this study aimed to analyze the BA association with single nucleotide polymorphisms (SNPs) and the additive influence of ADD3 and ADD3-AS1 in Thai neonates. METHODS: DNAs from 56 BA cases and 166 controls were genotyped for rs2501577, rs11194981, rs12268910 (ADD3) and rs17095355 (ADD3-AS1), using TaqMan PCR. Genotype distributions were compared between the groups, and SNP-SNP interactions were analyzed by combination of allelotypes. RESULTS: The risk allele frequencies of rs2501577, rs11194981, and rs17095355 in the BA group were significantly higher than in the controls. Univariate analysis showed that recessive variants in the three SNPs were associated with BA risk at ORs of 1.81 (95% CI 1.32-2.50), 1.58 (95% CI 1.14-2.20) and 1.92 (95% CI 1.39-2.66), respectively. SNP-SNP interaction analysis showed that the SNP combination of the two genes rs17095355 and rs2501577 provided an additive increase in BA risk. CONCLUSION: ADD3 and ADD3-AS1 variants increased susceptibility to BA, suggesting that these genes may play an additive role in the pathogenesis of the disease. In addition, these interactions may give a clue to the overexpression of the ADD3 protein in the liver of BA patients.

Asunto(s)

Atresia Biliar/genética , Proteínas de Unión a Calmodulina/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , ARN sin Sentido/genética , ARN Bacteriano/genética , Atresia Biliar/epidemiología , Proteínas de Unión a Calmodulina/metabolismo , Femenino , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Incidencia , Lactante , Masculino , Reacción en Cadena de la Polimerasa , ARN sin Sentido/metabolismo , Tailandia/epidemiología

Asunto(s)

Aberraciones Cromosómicas , Linfoma de Células B Grandes Difuso , Mieloma Múltiple , Humanos , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Mieloma Múltiple/patología

RESUMEN

OBJECTIVE: Recent studies have identified 10q24-rs17095355 as a susceptibility locus for biliary atresia (BA). To more precisely estimate the association between the rs17095355 polymorphism and BA risk, a meta-analysis was performed. METHODS: A comprehensive search was conducted to examine all the eligible studies by electronic databases including Elsevier Science Direct, Pubmed, Google Scholar, China National Knowledge Infrastructure (CNKI) and Chinese Biomedical Literature (CBM) up to December 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association. RESULTS: A total of 6 comparisons from 5 relevant studies involving 1000 patients and 3257 controls were included to analyze the association between rs17095355 and BA risk. The pooled OR for T allele of rs17095355 was 1.72 (95%CI 1.53-1.92, p < 0.01) in BA. Stratification by ethnicity indicated the degree of risk of rs17095355 with BA susceptibility was similar in populations of Asian origin. The pooled OR was 1.81 (95%CI 1.60-2.06, p < 0.01). CONCLUSIONS: This meta-analysis confirms the association of rs17095355 polymorphism and BA development, especially in Asians. More original studies with large sample are needed to replicate this genetic association in different ethnic groups.

Asunto(s)

Atresia Biliar/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Pueblo Asiatico/genética , Atresia Biliar/embriología , Estudios de Casos y Controles , China , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Embarazo

RESUMEN

We have reported that the myogenic response of the renal afferent arteriole (Af-art) and middle cerebral artery (MCA) and autoregulation of renal and cerebral blood flow are impaired in Fawn-Hooded Hypertensive (FHH) rats. Transfer of a region of chromosome 1 containing γ-adducin (Add3) from the Brown Norway rat rescued the vascular dysfunction and the development of renal disease. To examine whether Add3 is a viable candidate gene altering renal and cerebral hemodynamics in FHH rats, we knocked down the expression of Add3 in rat Af-arts and MCAs cultured for 36-h using a 27-mer Dicer-substrate short interfering RNA (DsiRNA). Control Af-arts constricted by 10 ± 1% in response to an elevation in pressure from 60 to 120 mmHg but dilated by 4 ± 3% when treated with Add3 DsiRNA. Add3 DsiRNA had no effect on the vasoconstrictor response of the Af-art to norepinephrine (10-7 M). Add3 DsiRNA had a similar effect on the attenuation of the myogenic response in the MCA. Peak potassium currents were threefold higher in smooth muscle cells isolated from Af-arts or MCAs transfected with Add3 DsiRNA than in nontransfected cells isolated from the same vessels. This is the first study demonstrating that Add3 plays a role in the regulation of potassium channel function and vascular reactivity. It supports the hypothesis that sequence variants in Add3, which we previously identified in FHH rats, may play a causal role in the impaired myogenic response and autoregulation in the renal and cerebral circulation.

Asunto(s)

Proteínas de Unión a Calmodulina/metabolismo , Técnicas de Silenciamiento del Gen , Hipertensión/metabolismo , Riñón/irrigación sanguínea , Músculo Liso Vascular/metabolismo , Interferencia de ARN , Vasoconstricción , Animales , Arteriolas/metabolismo , Arteriolas/fisiopatología , Proteínas de Unión a Calmodulina/genética , Línea Celular , Circulación Cerebrovascular , Modelos Animales de Enfermedad , Homeostasis , Hipertensión/genética , Hipertensión/fisiopatología , Masculino , Potenciales de la Membrana , Arteria Cerebral Media/metabolismo , Arteria Cerebral Media/fisiopatología , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Potasio/metabolismo , Ratas Sprague-Dawley , Circulación Renal , Técnicas de Cultivo de Tejidos , Transfección , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología

RESUMEN

AIM:To investigate the relationship between the expression of adducin 3 (ADD3) and its splicing isoforms and colorectal cancer (CRC).METHODS:The expression of ADD3, ADD3-Ia and ADD3-Ib in 50 pair of CRC tissues , 20 pairs of colorectal polyp tissues , and 2 CRC cell lines SW480 and SW620 before and after oxaliplatin or fluoroura-cil intervention were detected by real-time PCR.The cell activity was determined by MTT assay , the cell migration ability was evaluated by wound-healing assay , and the cell invasion ability was measured by Transwell assay .RESULTS:The expres-sion levels of ADD3 and ADD3-Ib were decreased in the CRC tissues as compared with the normal mucous (P<0.01), and ADD3-Ia/Ib ratio was increased in the CRC tissues (P<0.01).The expression level of ADD3-Ia was higher in T3-4 group than that in T1-2 group (P<0.05).Reduced expression of ADD3, ADD3-Ia and ADD3-Ib in colorectal polyps was observed compared with the normal tissues (P<0.01).Compared with the SW480 cells, the expression levels of ADD3-Ia and ADD3-Ib were lower (P<0.05) and the ADD3-Ia/Ib ratio was higher (P <0.01) in the SW620 cells.After treated with oxalipla-tin or fluorouracil, the cell activity, migration and invasion in the SW620 and SW480 cells were weakened accompanied by the increases in the expression levels of ADD 3, ADD3-Ia and ADD3-Ib to various certain extents .CONCLUSION:In CRC there is a tendency that ADD3-Ib reduction leads to ADD3 decrease, accompanied by an increased ADD3-Ia/Ib ratio.The expression changes of ADD 3 and its splicing isoforms in the CRC may be relevant to its invasion ability .