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1.
World J Gastroenterol ; 26(34): 5146-5155, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32982115

RESUMO

BACKGROUND: Endoscopy-based Kyoto classification for gastritis and pathological topographic distribution of neutrophil infiltration are correlated with gastric cancer risk. AIM: To investigate the association between Kyoto classification and the topographic distribution of neutrophil activity. METHODS: Kyoto classification score, ranging from 0 to 8, consisted of atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. Neutrophil activity was scored according to the updated Sydney System using biopsy samples obtained from the greater curvature of the corpus and the antrum. The participants were divided into four categories, inactive stomach, antrum-predominant gastritis, pangastritis, and corpus-predominant gastritis, based on the topographic distribution of neutrophil activity. Effects of sex, age, body mass index, drinking habit, smoking habit, family history of gastric cancer, serum Helicobacter pylori (H. pylori) antibody, and Kyoto score on topography of neutrophil infiltration were analyzed. RESULTS: A total of 327 patients (comprising 50.7% women, with an average age of 50.2 years) were enrolled in this study. H. pylori infection rate was 82.9% with a mean Kyoto score of 4.63. The Kyoto score was associated with the topographic distribution of neutrophil activity. Kyoto scores were significantly higher in the order of inactive stomach, antrum-predominant gastritis, pangastritis, and corpus-predominant gastritis (3.05, 4.57, 5.21, and 5.96, respectively). Each individual score of endoscopic findings (i.e., atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness) was correlated with the topographic distribution of neutrophil activity. On multivariate analysis, the Kyoto score, age, and serum H. pylori antibody were independently associated with the topographic distribution of neutrophil activity. CONCLUSION: The Kyoto classification score was associated with the topographic distribution of neutrophil activity.

2.
Nat Genet ; 52(7): 669-679, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32514122

RESUMO

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Estudos de Coortes , Feminino , Predisposição Genética para Doença/etnologia , Variação Genética , Humanos , Padrões de Herança , Japão , Masculino , Fatores Sexuais , Fatores de Transcrição/genética
3.
J Clin Invest ; 130(4): 1948-1960, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32149733

RESUMO

The major risk factor for kidney stone disease is idiopathic hypercalciuria. Recent evidence implicates a role for defective calcium reabsorption in the renal proximal tubule. We hypothesized that claudin-2, a paracellular cation channel protein, mediates proximal tubule calcium reabsorption. We found that claudin-2-null mice have hypercalciuria due to a primary defect in renal tubule calcium transport and papillary nephrocalcinosis that resembles the intratubular plugs in kidney stone formers. Our findings suggest that a proximal tubule defect in calcium reabsorption predisposes to papillary calcification, providing support for the vas washdown hypothesis. Claudin-2-null mice were also found to have increased net intestinal calcium absorption, but reduced paracellular calcium permeability in the colon, suggesting that this was due to reduced intestinal calcium secretion. Common genetic variants in the claudin-2 gene were associated with decreased tissue expression of claudin-2 and increased risk of kidney stones in 2 large population-based studies. Finally, we describe a family in which males with a rare missense variant in claudin-2 have marked hypercalciuria and kidney stone disease. Our findings indicate that claudin-2 is a key regulator of calcium excretion and a potential target for therapies to prevent kidney stones.

4.
Sci Rep ; 10(1): 1197, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31988393

RESUMO

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10-25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Coortes , Feminino , Genótipo , Humanos , Japão , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Homeostase do Telômero/genética
5.
Cancer Epidemiol Biomarkers Prev ; 29(2): 477-486, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31826910

RESUMO

BACKGROUND: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. METHODS: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. RESULTS: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10-8; rs62558833, P = 7.5 × 10-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. CONCLUSIONS: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. IMPACT: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

6.
Nat Commun ; 10(1): 5175, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729369

RESUMO

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45-60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted.


Assuntos
Cálcio/metabolismo , Cálculos Renais/genética , Vitamina D/metabolismo , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão , Cálculos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteínas/genética , Proteínas/metabolismo , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Reino Unido
7.
Sci Rep ; 9(1): 17332, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757997

RESUMO

Genome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P < 5.0 × 10-8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 (ALCAM) and rs75286142 on 21q22.12 (CLIC6-RUNX1). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population.


Assuntos
Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Antígenos CD/genética , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Canais de Cloreto/genética , Mapeamento Cromossômico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Proteínas Fetais/genética , Loci Gênicos , Predisposição Genética para Doença , Humanos , Japão , Desequilíbrio de Ligação
8.
Int J Oncol ; 54(6): 1907-1920, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081062

RESUMO

The p53 protein is a tumour suppressor and transcription factor that regulates the expression of target genes involved in numerous stress responses systems. In this study, we designed a screening strategy using DNA damage­induced mouse and human transcriptome data to identify novel downstream targets of p53. Our method selected genes with an induced expression in multiple organs of X­ray­irradiated p53 wild­type mice. The expression of inka box actin regulator 2 gene, known as Inka2, was upregulated in 12 organs when p53 expression was induced. Similarly, INKA2 was induced in a p53­dependent manner at both the mRNA and protein level in human cells treated with adriamycin. Reporter assays confirmed that p53 directly regulated INKA2 through an intronic binding site. The overexpression of INKA2 produced a slight decrease in cancer cell growth in the colony formation assay. Moreover, the analysis of The Cancer Genome Atlas (TCGA) data revealed a decreased INKA2 expression in tumour samples carrying p53 mutations compared with p53 wild­type samples. In addition, significantly higher levels of DNA methylation were observed in the INKA2 promoter in tumour samples, concordant with the reduced INKA2 expression in tumour tissues. These results demonstrate the potential of INKA2 as a cancer cell growth inhibitor. Furthermore, INKA2 protein interacts with the serine/threonine­protein kinase, p21 (RAC1) activated kinase (PAK)4, which phosphorylates ß­catenin to prevent ubiquitin­proteasomal degradation. As ß­catenin was downregulated in a stable INKA2­expressing cell line, the findings of this study suggest that INKA2 is a novel, direct downstream target of p53 that potentially decreases cell growth by inhibiting the PAK4­ß­catenin pathway.


Assuntos
Perfilação da Expressão Gênica/métodos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/genética , Proteína Supressora de Tumor p53/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Linhagem Celular Tumoral , Metilação de DNA , Doxorrubicina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Células HCT116 , Humanos , Camundongos , Mutação , Neoplasias/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Análise de Sequência de RNA/métodos , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , beta Catenina/metabolismo
9.
J Am Soc Nephrol ; 30(5): 855-864, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30975718

RESUMO

BACKGROUND: A family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci. METHODS: To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan. RESULTS: The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%). CONCLUSIONS: Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.


Assuntos
Cálcio/sangue , Loci Gênicos , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Ácido Úrico/sangue , Urolitíase/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Taxa de Filtração Glomerular , Humanos , Japão/epidemiologia , Masculino , Fenótipo , Prevalência , Medição de Risco , Urolitíase/fisiopatologia
10.
J Invest Dermatol ; 139(7): 1459-1469, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30684556

RESUMO

Identification of the specific genetic variants responsible for the increased susceptibility to familial or sporadic cancers is important. Using a forward genetics approach to map such loci in a mouse skin cancer model, we previously identified a strong genetic locus, Stmm3, conferring resistance to chemically induced skin papillomas on chromosome 4. Here, we report the cyclin-dependent kinase inhibitor gene Cdkn2a/p19Arf as a major responsible gene for the Stmm3 locus. We provide evidence that the function of Stmm3 is dependent on p53 and that p19ArfMSM confers stronger resistance to papillomas than p16Ink4aMSMin vivo. In addition, we found that genetic polymorphism in p19Arf between a resistant strain, MSM/Ms (Val), and a susceptible strain, FVB/N (Leu), alters the susceptibility to papilloma development, malignant conversion, and the epithelial-mesenchymal transition. Moreover, we demonstrated that the p19ArfMSM allele more efficiently activates the p53 pathway than the p19ArfFVB allele in vitro and in vivo. Furthermore, we found polymorphisms in CDKN2A in the vicinity of a polymorphism in mouse Cdkn2a associated with the risk of human cancers in the Japanese population. Genetic polymorphisms in Cdkn2a and CDKN2A may affect the cancer risk in both mice and humans.


Assuntos
Cromossomos Humanos Par 4/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Genótipo , Papiloma/genética , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/metabolismo , Alelos , Animais , Carcinogênese/genética , Modelos Animais de Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Camundongos , Camundongos Knockout , Papiloma/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/induzido quimicamente , Proteína Supressora de Tumor p53/genética
11.
J Urol ; 201(2): 386-392, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30063927

RESUMO

PURPOSE: We evaluated the association of hypospadias and 17 susceptibility loci previously identified by a European genome-wide association study in a cohort of Japanese patients. We also examined the expression of candidate genes in male mouse embryos to determine the possible underlying mechanisms of this disease. MATERIALS AND METHODS: We enrolled 169 Japanese patients (mean age at surgery 3.7 years) who underwent repair of hypospadias. Genotyping of 17 single nucleotide polymorphisms was performed using a multiplex polymerase chain reaction invader assay. We also performed in situ hybridization to determine whether candidate genes were expressed in the male genital tubercle during embryonic development of the external genitalia in mice. RESULTS: Single nucleotide polymorphism rs3816183 of HAAO was significantly associated with susceptibility to hypospadias in general (p = 0.0019) and to anterior/middle hypospadias (p = 0.0283) and posterior hypospadias (p = 0.0226), while single nucleotide polymorphism rs6499755 of IRX6 showed an association with susceptibility to anterior/middle hypospadias (p = 0.0472). In mouse embryos there was no significant upregulation of Haao expression in the developing male external genitalia. Irx3 and Irx5, which are linked to Irx6 within the IrxB cluster, were expressed in the mesenchyme remote from the urethral plate epithelium during the critical embryonic period for masculinization. Irx6 was expressed in the ectodermal epithelium, demonstrating prominent dorsal ectodermal expression without expression in the ventral ectoderm adjacent to the urethral plate during the same period. CONCLUSIONS: Genetic variations of HAAO and IRX6 influence susceptibility to hypospadias in the Japanese population. Further research is needed to clarify the mechanism by which variations in these genes contribute to the pathogenesis of hypospadias.


Assuntos
3-Hidroxiantranilato 3,4-Dioxigenase/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hipospadia/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , 3-Hidroxiantranilato 3,4-Dioxigenase/metabolismo , Adolescente , Animais , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Ectoderma/metabolismo , Embrião de Mamíferos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Camundongos , Camundongos Endogâmicos ICR , Organogênese/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Uretra/crescimento & desenvolvimento
12.
Gastroenterology ; 156(5): 1455-1466, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30529582

RESUMO

BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations. METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10-8. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci. CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to ß-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Ásia/epidemiologia , Estudos de Casos e Controles , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/imunologia , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Medição de Risco , Fatores de Risco
13.
PLoS One ; 13(12): e0209096, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30557369

RESUMO

Genome-wide association studies (GWAS) have identified greater than 30 variants associated with ovarian cancer, but most of these variants were investigated in European populations. Here, we integrated GWAS and subsequent functional analyses to identify the genetic variants with potential regulatory effects. We conducted GWAS for ovarian cancer using 681 Japanese cases and 17,492 controls and found that rs137672 on 22q13.1 exhibited a strong association with a P-value of 1.05 × 10(-7) and an odds ratio of 0.573 with a 95% confidence interval of 0.466-0.703. In addition, three previously reported SNPs, i.e., rs10088218, rs9870207 and rs1400482, were validated in the Japanese population (P < 0.05) with the same risk allele as noted in previous studies. Functional studies including regulatory feature analysis and electrophoretic mobility shift assay (EMSA) revealed two regulatory SNPs in 22q13.1, rs2072872 and rs6509, that affect the binding affinity to some nuclear proteins in ovarian cancer cells. The plausible regulatory proteins whose motifs could be affected by the allele changes of these two SNPs were also proposed. Moreover, the protective G allele of rs6509 was associated with a decreased SYNGR1 expression level in normal ovarian tissues. Our findings elucidated the regulatory variants in 22q13.1 that are associated with ovarian cancer risk.


Assuntos
Cromossomos Humanos Par 22/genética , Variação Genética , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Técnicas de Genotipagem , Humanos , Japão , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
14.
Cancer Sci ; 109(12): 4015-4024, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30281874

RESUMO

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10-8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10-10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10-13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10-11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.


Assuntos
Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 20/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Sistema ABO de Grupos Sanguíneos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 9/genética , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Infecções por Helicobacter/genética , Proteínas de Homeodomínio/genética , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/microbiologia , Adulto Jovem , beta-Defensinas/genética
15.
Oncotarget ; 9(3): 3936-3945, 2018 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-29423095

RESUMO

SNP rs2294008 in Prostate Stem Cell Antigen (PSCA) and decreased PSCA expression are associated with gastric cancer. The objective of this study is to investigate the role of rs2294008 and PSCA expression in the gastritis-gastric cancer carcinogenic pathway. We conducted a case-control association study of H. pylori-infected gastritis and gastric cancer. rs2294008 was associated with the progression to chronic active gastritis (P = 9.4 × 10-5; odds ratio = 3.88, TT + TC vs CC genotype), but not with H. pylori infection per se nor with the progression from active gastritis to gastric cancer. We also assessed the association of rs2294008 with PSCA mRNA expression in the gastric mucosa at various disease stages and found that rs2294008 was associated with PSCA expression (P = 1.3 × 10-12). H. pylori infection (P = 5.1 × 10-8) and eradication therapy (P < 1 × 10-11) resulted in the reduced and increased PSCA expression, respectively, indicating negative regulation of PSCA expression by H. pylori infection. PSCA expression was decreased in severe gastritis compared with mild gastritis only among T allele carriers. Our findings revealed the regulation of PSCA expression by host genetic variation and bacterial infection might contribute to gastritis progression after H. pylori infection.

16.
Cell Rep ; 22(6): 1473-1483, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29425503

RESUMO

Recent proteome analyses have provided a comprehensive overview of various posttranslational modifications (PTMs); however, PTMs involving protein citrullination remain unclear. We performed a proteomic analysis of citrullinated proteins, and we identified more than 100 PAD4 (peptidyl arginine deiminase 4) substrates. Approximately one-fifth of the PAD4 substrates contained an RG/RGG motif, and PAD4 competitively inhibited the methylation of the RGG motif in FET proteins (FUS, EWS, and TAF15) and hnRNPA1, which are causative genes for ALS (amyotrophic lateral sclerosis). PAD4-mediated citrullination significantly inhibited the aggregation of FET proteins, a frequently observed feature in neurodegenerative diseases. FUS protein levels in arsenic-induced stress granules were significantly increased in Padi4-/- mouse embryonic fibroblasts (MEFs). Moreover, rs2240335 was associated with low expression of PADI4 in the brain and a high risk of ALS (p = 0.0381 and odds ratio of 1.072). Our findings suggest that PAD4-mediated RGG citrullination plays a key role in protein solubility and ALS pathogenesis.


Assuntos
Esclerose Amiotrófica Lateral/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Desiminases de Arginina em Proteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Motivos de Aminoácidos , Esclerose Amiotrófica Lateral/patologia , Animais , Citrulinação , Humanos , Camundongos , Agregados Proteicos , Proteômica , Proteína EWS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Fatores Associados à Proteína de Ligação a TATA/metabolismo
17.
Carcinogenesis ; 39(5): 652-660, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29471430

RESUMO

Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Genome-wide association studies (GWAS) identified more than 50 CRC loci. However, most of the previous studies were conducted in European population, and host genetic factors among Japanese population are largely remained to be identified. To identify novel loci in the Japanese population, here, we performed a large-scale GWAS using 6692 cases and 27 178 controls followed by a replication analysis using more than 11 000 case-control samples. We found the significant association of 10 loci (P < 5 × 10-8), including 2 novel loci on 16q24.1 (IRF8-FOXF1, rs847208, P = 3.15 × 10-9 and odds ratio = 1.107 with 95% confidence interval (CI) of 1.071-1.145) and 20q13.12 (TOX2, rs6065668, P = 4.47 × 10-11 and odds ratio = 0.897 with 95% CI of 0.868-0.926). Moreover, 35 previously reported single nucleotide polymorphisms (SNPs) in 24 regions were validated in the Japanese population (P < 0.05) with the same risk allele as in the previous studies. SNP rs6065668 was significantly associated with TOX2 expression in the sigmoid colon. In addition, nucleotide substitutions in the regulatory region of TOX2 were predicted to alter the binding of several transcription factors, including KLF5. Our findings elucidate the important role of genetic variations in the development of CRC in the Japanese population.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
18.
Sci Rep ; 7(1): 10739, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28878391

RESUMO

p53 encodes a transcription factor that transactivates downstream target genes involved in tumour suppression. Although osteosarcoma frequently has p53 mutations, the role of p53 in osteosarcomagenesis is not fully understood. To explore p53-target genes comprehensively in calvarial bone and find out novel druggable p53 target genes for osteosarcoma, we performed RNA sequencing using the calvarial bone and 23 other tissues from p53 +/+ and p53 -/- mice after radiation exposure. Of 23,813 genes, 69 genes were induced more than two-fold in irradiated p53 +/+ calvarial bone, and 127 genes were repressed. Pathway analysis of the p53-induced genes showed that genes associated with cytokine-cytokine receptor interactions were enriched. Three genes, CD137L, CDC42 binding protein kinase gamma and Follistatin, were identified as novel direct p53 target genes that exhibited growth-suppressive effects on osteosarcoma cell lines. Of the three genes, costimulatory molecule Cd137l was induced only in calvarial bone among the 24 tissues tested. CD137L-expressing cells exhibited growth-suppressive effects in vivo. In addition, recombinant Fc-fusion Cd137l protein activated the immune response in vitro and suppressed osteosarcoma cell growth in vivo. We clarified the role of CD137L in osteosarcomagenesis and its potential therapeutic application. Our transcriptome analysis also indicated the regulation of the immune response through p53.


Assuntos
Ligante 4-1BB/metabolismo , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Imunomodulação , Osteossarcoma/imunologia , Osteossarcoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ligante 4-1BB/genética , Animais , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Osteossarcoma/genética , Ligação Proteica , Proteína Supressora de Tumor p53/genética
19.
Oncotarget ; 8(34): 55790-55803, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28915553

RESUMO

p53 mutation is a marker of poor prognosis in breast cancers. To identify downstream targets of p53, we screened two transcriptome datasets, including cDNA microarrays of MCF10A breast epithelial cells with wild-type p53 or p53-null background, and RNA sequence analysis of breast invasive carcinoma. Here, we unveil ten novel p53 target candidates that are up-regulated after the induction of p53 in wild-type cells. Their expressions are also high in breast invasive carcinoma tissues with wild-type p53. The GO analysis identified epidermis development and ectoderm development, which COL17A1 participates, as significantly up-regulated by wild-type p53. The COL17A1 expressions increased in a p53-dependent manner in human breast cells and mouse mammary tissues. Reporter assay and ChIP assay identified intronic p53-binding sequences in the COL17A1 gene. The MDA-MB-231 cells that genetically over-express COL17A1 gene product exhibited reduced migration and invasion in vitro. Similarly, COL17A1 expression was decreased in metastatic tumors compared to primary tumors and normal tissues, even from the same patients. Moreover, high COL17A1 expression was associated with longer survival of patients with invasive breast carcinoma. In conclusion, we revealed that COL17A1 is a novel p53 transcriptional target in breast tissues that inhibits cell migration and invasion and is associated with better prognosis.

20.
Oncotarget ; 8(34): 55821-55836, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28915555

RESUMO

The p53 protein is a sophisticated transcription factor that regulates dozens of target genes simultaneously in accordance with the cellular circumstances. Although considerable efforts have been made to elucidate the functions of p53-induced genes, a holistic understanding of the orchestrated signaling network repressed by p53 remains elusive. Here, we performed a systematic analysis to identify simultaneously regulated p53-repressed genes in breast cancer cells. Consequently, 28 genes were designated as the p53-repressed gene module, whose gene components were simultaneously suppressed in breast cancer cells treated with Adriamycin. A ChIP-seq database showed that p53 does not preferably bind to the region around the transcription start site of the p53-repressed gene module elements compared with that of p53-induced genes. Furthermore, we demonstrated that p21/CDKN1A plays a pivotal role in the suppression of the p53-repressed gene module in breast cancer cells. Finally, we showed that appropriate suppression of some genes belonging to the p53-repressed gene module contributed to a better prognosis of breast cancer patients. Taken together, these findings disentangle the gene regulatory network underlying the built-in p53-mediated tumor suppression system.

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