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By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.
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Neoplasias de la Mama , Estudio de Asociación del Genoma Completo , Femenino , Humanos , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Transcriptoma/genética , Neoplasias de la Mama/genética , Estudios de Casos y ControlesRESUMEN
Overweight and obese are risk factors for various diseases. In Taiwan, the combined prevalence of overweight and obesity has increased dramatically. Here, we conducted a genome-wide association study (GWAS) on four adiposity traits, including body-mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-hip ratio (WHR), using the data for more than 21,000 subjects in Taiwan Biobank. Associations were evaluated between 6,546,460 single-nucleotide polymorphisms (SNPs) and adiposity traits, yielding 13 genome-wide significant (GWS) adiposity-associated trait-loci pairs. A known gene, FTO, as well as two BF%-associated loci (GNPDA2-GABRG1 [4p12] and RNU6-2-PIAS1 [15q23]) were identified as pleiotropic effects. Moreover, RALGAPA1 was found as a specific genetic predisposing factor to high BMI in a Taiwanese population. Compared to other populations, a slightly lower heritability of the four adiposity traits was found in our cohort. Surprisingly, we uncovered the importance of neural pathways that might influence BF%, WC and WHR in the Taiwanese (East Asian) population. Additionally, a moderate genetic correlation between the WHR and BMI (γg = 0.52; p = 2.37×10-9) was detected, suggesting different genetic determinants exist for abdominal adiposity and overall adiposity. In conclusion, the obesity-related genetic loci identified here provide new insights into the genetic underpinnings of adiposity in the Taiwanese population.
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Adiposidad/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Adulto , Bancos de Muestras Biológicas , Estudios de Cohortes , Femenino , Proteínas Activadoras de GTPasa/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Obesidad/genética , Sobrepeso/genética , Polimorfismo de Nucleótido Simple , TaiwánRESUMEN
BACKGROUND: This study aimed to validate self-reported medical conditions in the Taiwan Biobank (TWBB), in which participants were inquired about 30 disease conditions, by comparing them with claims records from Taiwan's National Health Insurance (NHI) claims database. METHODS: We identified 30 clinical diagnoses using ICD-CM codes from ambulatory and hospital claims within the NHI claims database, matching diseases included in the TWBB. The concordance between self-reports and claims records was evaluated using tetrachoric correlation to assess the correlation between binary variables. RESULTS: A total of 131,834 participants aged 30-70 years with data from the TWBB and NHI records were included. Concordance analysis revealed tetrachoric correlations ranged from 0.420 (chronic obstructive pulmonary disease) to 0.970 (multiple sclerosis). However, several disorders exhibited lower tetrachoric correlations. The concordance was higher among those with higher education attainment, and lower among married individuals. CONCLUSION: The concordance between self-reports in the TWBB and NHI claims records varied across clinical diagnoses, showing inconsistencies depending on participant characteristics. These findings underscore the need for further investigation, especially when these variables are crucial to research objectives. Integrating complementary databases such as clinical diagnoses, prescription records, and medical procedures can enhance accuracy through customized algorithms based on disease categories and participant characteristics and optimize sensitivity or positive predictive values to align with specific research objectives.
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Objective To evaluate the effect of surgical treatment on extracranial supra-aortic aneurysms and summarize the experience.Methods The clinical data of 10 patients undergoing surgical treatment of extracranial supra-aortic aneurysms from May 2019 to November 2023 in the Department of Vascular Surgery of Beijing Tiantan Hospital affiliated to Capital Medical University were collected.The 10 patients included 5 patients with internal carotid artery aneurysm,2 patients with subclavian artery aneurysm,2 patients with vertebral artery aneurysm,and 1 patient with internal carotid artery aneurysm combined with ipsilateral subclavian artery aneurysm.The surgical indications,surgical regimens,clinical efficacy,and complications were retrospectively analyzed. Results All the 10 patients underwent surgery successfully,with the surgery duration range of 60-420 min and the median surgery duration of 180.0 (121.5,307.5) min.Intraoperative bleeding volume varied within 30-400 mL,with a median of 90 (50,125) mL.The time of carotid artery blocking and vertebral artery blocking varied within the ranges of 10-20 min and 20-30 min,with the medians of 15.0 (11.5,16.3) min and 25.0 (15.0,22.5) min,respectively.No cardiac accident,cerebral infarction,or cerebral hemorrhage occurred during the perioperative period.The 10 patients were followed up for 3-58 months,with the median follow-up time of 8.5 (5.3,17.0) months.One patient with subclavian artery aneurysm developed artificial vessel occlusion 20 months after surgery.One patient with internal carotid artery aneurysm developed distal carotid artery stenosis 6 months after surgery. Conclusion Surgical treatment should be actively adopted for extracranial supra-aortic aneurysms,and individualized surgical regimens should be designed according to patient conditions.
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Patients with severe COVID-19 often suffer from lymphopenia, which is linked to T-cell sequestration, cytokine storm, and mortality. However, it remains largely unknown how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces lymphopenia. Here, we studied the transcriptomic profile and epigenomic alterations involved in cytokine production by SARS-CoV-2-infected cells. We adopted a reverse time-order gene coexpression network approach to analyze time-series RNA-sequencing data, revealing epigenetic modifications at the late stage of viral egress. Furthermore, we identified SARS-CoV-2-activated nuclear factor-κB (NF-κB) and interferon regulatory factor 1 (IRF1) pathways contributing to viral infection and COVID-19 severity through epigenetic analysis of H3K4me3 chromatin immunoprecipitation sequencing. Cross-referencing our transcriptomic and epigenomic data sets revealed that coupling NF-κB and IRF1 pathways mediate programmed death ligand-1 (PD-L1) immunosuppressive programs. Interestingly, we observed higher PD-L1 expression in Omicron-infected cells than SARS-CoV-2 infected cells. Blocking PD-L1 at an early stage of virally-infected AAV-hACE2 mice significantly recovered lymphocyte counts and lowered inflammatory cytokine levels. Our findings indicate that targeting the SARS-CoV-2-mediated NF-κB and IRF1-PD-L1 axis may represent an alternative strategy to reduce COVID-19 severity.
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COVID-19 , Linfopenia , Animales , Ratones , SARS-CoV-2/metabolismo , Antígeno B7-H1 , Evasión Inmune , FN-kappa B/metabolismo , Regulación hacia Arriba , Citocinas/metabolismoRESUMEN
INTRODUCTION: Chronic kidney disease, which is defined by a reduced estimated glomerular filtration rate and albuminuria, imposes a large health burden worldwide. Ethnicity-specific associations are frequently observed in genome-wide association studies (GWAS). This study conducts a GWAS of albuminuria in the nondiabetic population of Taiwan. METHODS: Nondiabetic individuals aged 30-70 years without a history of cancer were enrolled from the Taiwan Biobank. A total of 6,768 subjects were subjected to a spot urine examination. After quality control using PLINK and imputation using SHAPEIT and IMPUTE2, a total of 3,638,350 single-nucleotide polymorphisms (SNPs) remained for testing. SNPs with a minor allele frequency of less than 0.1% were excluded. Linear regression was used to determine the relationship between SNPs and log urine albumin-to-creatinine ratio. RESULTS: Six suggestive loci are identified in or near the FCRL3 (p = 2.56 × 10-6), TMEM161 (p = 4.43 × 10-6), EFCAB1 (p = 2.03 × 10-6), ELMOD1 (p = 2.97 × 10-6), RYR3 (p = 1.34 × 10-6), and PIEZO2 (p = 2.19 × 10-7). Genetic variants in the FCRL3 gene that encode a secretory IgA receptor are found to be associated with IgA nephropathy, which can manifest as proteinuria. The PIEZO2 gene encodes a sensor for mechanical forces in mesangial cells and renin-producing cells. Five SNPs with a p-value between 5 × 10-6 and 5 × 10-5 are also identified in five genes that may have a biological role in the development of albuminuria. CONCLUSION: Five new loci and one known suggestive locus for albuminuria are identified in the nondiabetic Taiwanese population.
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Glomerulonefritis por IGA , Insuficiencia Renal Crónica , Humanos , Estudio de Asociación del Genoma Completo , Albuminuria/genética , Albuminuria/epidemiología , Pruebas de Función Renal , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: We sought to investigate the midterm results of kissing self-expanding covered stents (SECSs) for the reconstruction of aortic bifurcation in complex aortoiliac occlusive disease. METHODS: Data of consecutive patients who had undergone endovascular treatment for aortoiliac occlusive disease were screened. Only patients with TransAtlantic Inter-Society Consensus (TASC) class C and D lesions treated by bilateral iliac kissing stents (KSs) were included. Midterm primary patency, risk factors, and limb salvage rates were analyzed. Follow-up results were analyzed using the Kaplan-Meier curves. Cox proportional hazards models were used to identify the predictors of primary patency. RESULTS: A total of 48 patients (95.8% men; mean age, 65.3 ± 10.2 years) were treated with kissing SECSs. Of them, 17 patients had TASC-II class C lesions and 31 had class D lesions. There were 38 total occlusive lesions, with a mean occlusive lesion length of 108.2 ± 57.3 mm. The overall mean lesion length was 140.3 ± 60.5 mm, and the mean length of implanted stents in the aortoiliac arteries was 141.9 ± 59.9 mm. The mean diameter of the deployed SECSs was 7.8 ± 0.5 mm. The mean follow-up time was 36.5 ± 15.8 months, and the follow-up rate was 95.8%. At 36 months, the overall primary patency, assisted primary patency, secondary patency, and limb salvage rates were 92.2%, 95.7%, 97.8%, and 100%, respectively. Univariate Cox regression analysis revealed that stent diameter ≤7 mm (hazard ratio [HR]: 9.53; 95% confidence interval [CI] 1.56-57.94, P = 0.014) and severe calcification (HR: 12.66; 95% CI 2.04-78.45, P = 0.006) were significantly associated with restenosis. Multivariate analysis showed severe calcification to be the only significant determinant of restenosis (HR: 12.66; 95% CI 2.04-78.45, P = 0.006). CONCLUSIONS: Kissing SECSs provide good midterm results for the treatment of aortoiliac occlusive disease. A stent diameter >7 mm is a potent protective factor against restenosis. Because severe calcification appears to be the only significant determinant of restenosis, patients with severe calcification require close follow-up.
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Enfermedades de la Aorta , Arteriopatías Oclusivas , Aterosclerosis , Calcinosis , Síndrome de Leriche , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Arteriopatías Oclusivas/diagnóstico por imagen , Arteriopatías Oclusivas/cirugía , Resultado del Tratamiento , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/cirugía , Arteria Ilíaca/diagnóstico por imagen , Arteria Ilíaca/cirugía , Factores de Tiempo , Factores de Riesgo , Stents , Grado de Desobstrucción Vascular , Aorta Abdominal , Estudios RetrospectivosRESUMEN
The Taiwanese people are composed of diverse indigenous populations and the Taiwanese Han. About 95% of the Taiwanese identify themselves as Taiwanese Han, but this may not be a homogeneous population because they migrated to the island from various regions of continental East Asia over a period of 400 years. Little is known about the underlying patterns of genetic ancestry, population admixture, and evolutionary adaptation in the Taiwanese Han people. Here, we analyzed the whole-genome single-nucleotide polymorphism genotyping data from 14,401 individuals of Taiwanese Han collected by the Taiwan Biobank and the whole-genome sequencing data for a subset of 772 people. We detected four major genetic ancestries with distinct geographic distributions (i.e., Northern, Southeastern, Japonic, and Island Southeast Asian ancestries) and signatures of population mixture contributing to the genomes of Taiwanese Han. We further scanned for signatures of positive natural selection that caused unusually long-range haplotypes and elevations of hitchhiked variants. As a result, we identified 16 candidate loci in which selection signals can be unambiguously localized at five single genes: CTNNA2, LRP1B, CSNK1G3, ASTN2, and NEO1. Statistical associations were examined in 16 metabolic-related traits to further elucidate the functional effects of each candidate gene. All five genes appear to have pleiotropic connections to various types of disease susceptibility and significant associations with at least one metabolic-related trait. Together, our results provide critical insights for understanding the evolutionary history and adaption of the Taiwanese Han population.
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Pueblo Asiatico , Genoma , Pueblo Asiatico/genética , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.
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Neoplasias de la Mama , Teorema de Bayes , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial/genética , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma. APPROACH AND RESULTS: Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P < 0.001; nonusers as a reference). Cancer-specific mortality was lower with postdiagnosis aspirin use in patients with all major BTC subtypes. CONCLUSIONS: The nationwide study revealed that postdiagnosis aspirin use was associated with improved BTC-specific mortality of various subtypes. The findings suggest that additional randomized trials are required to investigate aspirin's efficacy in BTC.
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Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Neoplasias de los Conductos Biliares/mortalidad , Colangiocarcinoma/mortalidad , Neoplasias del Conducto Colédoco/mortalidad , Neoplasias de la Vesícula Biliar/mortalidad , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática , Neoplasias de los Conductos Biliares/diagnóstico , Conductos Biliares Extrahepáticos , Conductos Biliares Intrahepáticos , Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/mortalidad , Carcinoma/diagnóstico , Carcinoma/mortalidad , Colangiocarcinoma/diagnóstico , Estudios de Cohortes , Neoplasias del Conducto Colédoco/diagnóstico , Femenino , Neoplasias de la Vesícula Biliar/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores ProtectoresRESUMEN
The stemness and metastasis of cancer cells are crucial features in determining cancer progression. Argonaute-2 (AGO2) overexpression was reported to be associated with microRNA (miRNA) biogenesis, supporting the self-renewal and differentiation characteristics of cancer stem cells (CSCs). Ursolic acid (UA), a triterpene compound, has multiple biological functions, including anticancer activity. In this study, we find that UA inhibits the proliferation of MDA-MB-231 and MCF-7 breast cancer cell lines using the CCK-8 assay. UA induced a significant decrease in the fraction of CSC in which it was examined by changes in the expression of stemness biomarkers, including the Nanog and Oct4 genes. UA altered invasion and migration capacities by significant decreases in the levels of epithelial-to-mesenchymal transition (EMT) proteins of slug and vimentin. Furthermore, the co-reduction in oncogenic miRNA levels (miR-9 and miR-221) was a result of the down-modulation in AGO2 in breast cancer cells in vitro. Mechanically, UA increases PTEN expression to inactivate the FAK/PI3K/Akt/mTOR signaling pathway and the decreased level of c-Myc in quantitative RT-PCR and Western blot imaging analyses. Our current understanding of the anticancer potential of UA in interrupting between EMT programming and the state of CSC suggests that UA can contribute to improvements in the clinical practice of breast cancer.
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Neoplasias de la Mama , MicroARNs , Triterpenos , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Línea Celular Tumoral , MicroARNs/metabolismo , Triterpenos/farmacología , Triterpenos/metabolismo , Transición Epitelial-Mesenquimal/genética , Células Madre Neoplásicas/metabolismo , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Ácido UrsólicoRESUMEN
Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs <10-5 were further tested for associations with serial ALT levels then validated in 486 anti-HCV seropositives. Multinomial logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals of SNPs associated with ALT. The SNP was evaluated for HCC risk by using Cox's proportional hazards models. After quality control, 803 participants with 564,464 SNPs were included in the analysis. Of these, 12 SNPs were associated with ALT (p < 10-5 ). Among the participants, 158 (19.7%) had ALT persistently ≤15 U/L, 327 (40.7%) ever >15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p < .05). The A allele (vs C) of rs568800 was associated with ALT >15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.
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Carcinoma Hepatocelular , Hepatitis C , Neoplasias Hepáticas , Alanina Transaminasa , Carcinoma Hepatocelular/genética , Estudio de Asociación del Genoma Completo , Hepacivirus/genética , Hepatitis C/genética , Humanos , Neoplasias Hepáticas/genéticaRESUMEN
PURPOSE: Magnesium-based alloy scaffold is a promising biodegradable stent due to its intrinsic mechanical performance and biocompatibility. Based on our preliminary experiments, we designed a novel sirolimus-eluting magnesium-based alloy scaffold. This work aimed to assess its safety and degradation performance in vivo. METHODS: The scaffolds were implanted in the lower limb arteries of Bama mini-pigs. Safety was defined as no immediate thrombosis or >30% residual stenosis, which was assessed with optical coherence tomography and digital subtraction angiography. Blood biochemical analyses were performed to evaluate hepatorenal toxicity. The degradation process of the scaffolds, the endothelialization, and lumen loss of the stented-vessels were detected with scanning electron microscopy, immunohistochemical, hematoxylin-eosin staining and optical coherence tomography. RESULTS: Twenty-four scaffolds were successfully implanted in six pigs with no signs of immediate thrombosis or >30% residual stenosis. The scaffolds were covered by endothelium at one month and absolutely resorbed at six months post implantation. Blood analysis showed that the hepatorenal function except for alanine aminotransferase and γ-glutamyl transpeptidase was normal. Obvious intimal hyperplasia and lumen loss were found in the stented vessels at three months, while the diameters and inner lumen areas of stented segments had increased significantly at six months (p.
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Magnesio , Sirolimus , Implantes Absorbibles , Aleaciones , Animales , Arterias , Angiografía Coronaria , Vasos Coronarios , Porcinos , Porcinos EnanosRESUMEN
Most genome-wide association studies (GWASs) identify genetic variants for breast cancer occurrence. In contrast, few are for recurrence and mortality. We conducted a GWAS on breast cancer survival after diagnosis in estrogen receptor-positive patients, including 953 Taiwanese patients with 159 events. Through Cox proportional hazard models estimation, we identified 24 risk SNPs with p < 1 × 10-5 . Based on imputation and integrated analysis, one SNP, rs1024176 (located in 1q24.2, p = 2.43 × 10-5 ) was found to be a functional variant associated with breast cancer survival and XCL1 gene expression. A series of experimental approaches, including cell-based analyses and CRISPR/Cas9 genome-editing system, were then used and identified the transcription factor MYBL2 was able to discriminately bind to the A allele of rs1024176, the protective variant for breast cancer survival, which promoted XCL1 expression, but not to the G allele of rs1024176. The chemokine XCL1 attracts type 1 dendritic cells (DC1s) to the tumor microenvironment. In breast cancer tissues, we applied a two-step Mendelian randomization analysis, using expression quantitative trait loci as instrumental variables, to confirm higher XCL1 expression was correlated with higher DC1 signatures and favorable disease progression, through the causal effect of rs1024176-A allele. Our study supports the genetic effect on preventing breast cancer survival through XCL1-induced DC1 recruitment in tumor microenvironment.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Quimiocinas C/genética , Quimiocinas C/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Quimiocinas C/biosíntesis , Células Dendríticas/inmunología , Células Dendríticas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Sitios de Carácter Cuantitativo , Transactivadores/genética , Transactivadores/inmunología , Adulto JovenRESUMEN
XRCC1 is an essential scaffold protein for base excision repair (BER) and helps to maintain genomic stability. XRCC1 has been indicated as a substrate for small ubiquitin-like modifier modification (SUMOylation); however, how XRCC1 SUMOylation is regulated in cells and how SUMOylated XRCC1 regulates BER activity are not well understood. Here, we show that SUMOylation of XRCC1 is regulated in cells under methyl-methanesulfonate (MMS) treatment and facilitates BER. Poly(ADP-ribose) polymerase 1 (PARP1) is activated by MMS immediately and synthesizes poly(ADP-ribose) (PAR), which in turn promotes recruitment of SUMO E3 TOPORS to XRCC1 and facilitates XRCC1 SUMOylation. A SUMOylation-defective mutant of XRCC1 had lower binding activity for DNA polymerase beta (POLB) and was linked to a lower capacity for repair of MMS-induced DNA damages. Our study therefore identified a pathway in which DNA damage-induced poly(ADP-ribosyl)ation (PARylation) promotes SUMOylation of XRCC1, which leads to more efficient recruitment of POLB to complete BER.
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ADN Polimerasa beta/genética , Poli ADP Ribosilación/genética , Sumoilación/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Oxidorreductasas de Alcohol/genética , Daño del ADN/efectos de los fármacos , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Inestabilidad Genómica/genética , Humanos , Metilmetanosulfonato/farmacología , Poli(ADP-Ribosa) Polimerasa-1/genética , Unión Proteica/genéticaRESUMEN
An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB1*03:01, DRB1*04:05, DQA1*03:03, and DQB1*04:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.
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Artritis Reumatoide/genética , Genética de Población , Antígenos HLA/genética , Polimorfismo de Nucleótido Simple , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Bases de Datos Genéticas , Genotipo , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fenotipo , Reproducibilidad de los Resultados , Taiwán , Secuenciación Completa del GenomaRESUMEN
The anti-tumor activity of diosgenin, a new steroidal constituent present in fenugreek, on two human breast cancer cell lines, MCF-7 and Hs578T, was studied. Diosgenin treatment resulted in cell growth inhibition, cell cycle arrest, and apoptosis in concentration- and time-dependent manners in both cell lines. Western blot analyses of whole cell lysates for cell cycle proteins showed that diosgenin altered phosphorylated cyclin checkpoint1 (p-Chk1Ser345) and cyclin B expression, which resulted in G2/M phase blockade. Mechanistically, Cdc25C-Cdc2 signaling was involved in inactivating Chk1Ser345 by p53-dependence in MCF-7 cells and p21-dependence in Hs578T cells that are p53-deficient. Moreover, diosgenin induced a significant loss of the mitochondrial membrane potential in breast cancer cells, and prominently affected cell death through down-regulation of the anti-apoptotic protein, Bcl-2. This released cytochrome c and activated the caspase signaling cascade. Taken together, these findings reveal that the anti-proliferative activity of diosgenin involves the induction of G2/M phase arrest via modulating the Cdc25C-Cdc2-cyclin B pathway and mitochondria-mediated apoptosis in human breast cancer cell lines. This suggests the potential usefulness of diosgenin in treating breast cancer.
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Apoptosis/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Diosgenina/farmacología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Fosfatasas cdc25/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Ciclina B/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
The Taiwan Biobank (TWB) aims to build a nationwide research database that integrates genomic/epigenomic profiles, lifestyle patterns, dietary habits, environmental exposure history and long-term health outcomes of 300,000 residents of Taiwan. We describe here an investigation of the population structure of Han Chinese on this Pacific island using genotype data of 591,048 SNPs in an initial freeze of 10,801 unrelated TWB participants. In addition to the North-South cline reported in other Han Chinese populations, we find the Taiwanese Han Chinese clustered into three cline groups: 5% were of northern Han Chinese ancestry, 79.9% were of southern Han Chinese ancestry, and 14.5% belonged to a third (T) group. We also find that this T group is genetically distinct from neighbouring Southeast Asians and Austronesian tribes but similar to other southern Han Chinese. Interestingly, high degree of LD between HLA haplotype A*33:03-B*58:01, an MHC allele being of pathological relevance, and SNPs across the MHC region was observed in subjects with T origin, but not in other Han Chinese. This suggested the T group individuals may have experienced evolutionary events independent from the other southern Han Chinese. Based on the newly-discovered population structure, we detect different loci susceptible to type II diabetes in individuals with southern and northern Han Chinese ancestries. Finally, as one of the largest dataset currently available for the Chinese population, genome-wide statistics for the 10,810 subjects are made publicly accessible through Taiwan View (https://taiwanview.twbiobank.org.tw/index; date last accessed October 14, 2016) to encourage future genetic research and collaborations with the island Taiwan.
Asunto(s)
Pueblo Asiatico/genética , Genética de Población , Polimorfismo de Nucleótido Simple/genética , Bancos de Muestras Biológicas , China , Femenino , Genotipo , Antígenos HLA-A/genética , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento , Masculino , TaiwánRESUMEN
Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have been shown to play an important role in breast cancer aetiology. We conducted a two-stage genome-wide association study (GWAS) including 14 224 cases and 14 829 controls of East Asian women to search for novel genetic susceptibility loci for breast cancer. Single nucleotide polymorphisms (SNPs) in two loci were found to be associated with breast cancer risk at the genome-wide significance level. The first locus, represented by rs12118297 at 1p22.3 (near the LMO4 gene), was associated with breast cancer risk with odds ratio (OR) and (95% confidence interval (CI)) of 0.91 (0.88-0.94) and a P-value of 4.48 × 10- 8 This association was replicated in another study, DRIVE GAME-ON Consortium, including 16 003 cases and 41 335 controls of European ancestry (OR = 0.95, 95% CI = 0.91-0.99, P-value = 0.019). The second locus, rs16992204 at 21q22.12 (near the LINC00160 gene), was associated with breast cancer risk with OR (95% CI) of 1.13 (1.07-1.18) and a P-value of 4.63 × 10 - 8 The risk allele frequency for this SNP is zero in European-ancestry populations in 1000 Genomes Project and thus its association with breast cancer risk cannot be assessed in DRIVE GAME-ON Consortium. Functional annotation using the ENCODE data indicates that rs12118297 might be located in a repressed element and locus 21q22.12 may affect breast cancer risk through regulating LINC00160 expressions and interaction with oestrogen receptor signalling. Our findings provide additional insights into the genetics of breast cancer.
Asunto(s)
Pueblo Asiatico/genética , Neoplasias de la Mama/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Neoplasias de la Mama/epidemiología , Asia Oriental , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Background /Aims: Recent studies of microRNA (miRNA) involvement in tumorigenesis have indicated the critical role of these non-coding small RNAs in malignant transformation, but the prognostic role, if any, of miRNAs in breast cancer remains undetermined. Therefore, we assessed the prognostic significance of microRNA-9 (miR-9) and miR-221 in breast cancer toward the goal of understanding the contribution(s) of these miRNAs to cancer cell stemness. METHODS: The level of each of miR-9 and miR-221 in 206 paired laser capture microdissected tumor cells and non-tumor cells was determined by quantitative reverse transcription-PCR (qRT-PCR). The relationship between the miRNA signature and clinicopathological data and prognosis of breast cancer was assessed. Identification of a stem cell-enriched side population was achieved with fluorescence-activated cell sorting and a sphere-forming assay. Wound healing, Boyden chamber assays, and western blotting were used to study the contribution of each miRNA to tumor cell migration and invasion. RESULTS: We found that induction of miR-9 and miR-221 mimics conferred side-population cells to form spheroidal tumor colonies in suspension culture that maintained the mesenchymal stem-cell potential in non-invasive MCF-7 breast cancer cells. In contrast, knockdown of both miR-9 and miR-221 in invasive MDA-MB-231 breast cancer cells dramatically decreased the number of side-population colonies with stem cell-like potency, which reduced the capacity for tumor-cell renewal, invasion, and migration. Clinically, the mean proportion of miR-9- or miR-221-overexpressing cells was significantly greater in tumor cells compared with non-tumor cells (P < 0.05). Increased levels of miR-9 and miR-221 in breast tissue portended a significantly elevated risk of progression to malignancy with respect to larger tumor size, poor differentiation, late-stage evolution, lymph-node metastasis (P < 0.05), and lower overall survival (Ptrend = 0.017; eight-year follow-up). CONCLUSION: Our findings provide strong evidence that miR-9 and miR-221 can enhance the generation of cancer stem cells to yield an invasive phenotype and that overexpression of these miRNAs predicts a poor outcome for breast cancer patients.