RESUMEN
Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.
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Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Niño , Humanos , Estudio de Asociación del Genoma Completo , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Factores de Transcripción/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genéticaAsunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Japón/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: The increasing number of dementia patients has become a global social problem. Amino acids are known to be used as precursors of neurotransmitters in the brain. Amino acid mixtures as a supplement may be used as a solution to Alzheimer's symptoms. This exploratory study evaluated the efficacy and safety of a mixture containing nine essential amino acids on behavioral and psychological symptoms of dementia (BPSD) and cognitive function in patients with Alzheimer's disease (AD). DESIGN: We conducted a double-blind, randomized, placebo-controlled trial to evaluate the intervention effects of nine essential amino acid mixture for 28 days. A total of 36 patients with AD were enrolled in Japan. BPSD and cognitive function were evaluated by the Neuropsychiatric Inventory-12 item (NPI-12; the primary endpoint), Mini-Mental State Examination (MMSE), Trail Making Test A (TMT-A), Trail Making Test B (TMT-B), Frontal Assessment Battery (FAB), and Clinical Dementia Rating Scale (CDR). RESULTS: Compared with placebo, the amino acid mixture did not improve NPI-12, MMSE, TMT-A and B or CDR scores. However, the analysis of covariance revealed improved FAB scores in the amino acid mixture group as a secondary endpoint. There were four subjects with adverse events in each group. CONCLUSIONS: Our results did not show a beneficial effect of the mixture containing nine essential amino acids on BPSD as a primary endpoint; however, it may improve executive function in patients with AD.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/psicología , Aminoácidos/uso terapéutico , Aminoácidos Esenciales/uso terapéutico , Cognición , Método Doble Ciego , Función Ejecutiva , HumanosRESUMEN
Prolonged isolated thrombocytopenia (PIT) is a complication following allogeneic hematopoietic cell transplantation that results in prolonged transfusion dependence. Recently, the efficacy of a thrombopoietin receptor agonist (eltrombopag) against PIT has been reported in adults; however, there are few reports in children. A 4-year-old male pediatric patient diagnosed with congenital pure red cell aplasia underwent allogeneic hematopoietic cell transplantation. Neutrophil engraftment was observed on post-transplant Day 26; however, platelet counts remained <10 × 109/L. Transfusions were required 1−2 times a week for at least 4 months. On post-transplant Day 124, oral eltrombopag (up to 2.4 mg/kg/day) was initiated. Thereafter, the platelet counts were maintained at ≥10 × 109/L, and the patient became transfusion independent. At 2 years and 6 months after the oral administration, no chromosomal abnormalities, thromboembolism, or myelofibrosis was observed. Thus, eltrombopag can be a potential treatment option for pediatric PIT.
RESUMEN
Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, ß = -10.99, p = 3.7 × 10-13 ). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10-6 ) and CHST11 (rs1148407, p = 2.09 × 10-6 ), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6-MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions (padjust = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6-MP tolerable dose in children in Japan.
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Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Pirofosfatasas , Antimetabolitos Antineoplásicos/uso terapéutico , Niño , Estudio de Asociación del Genoma Completo , Humanos , Japón , Mercaptopurina/uso terapéutico , Metiltransferasas/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatasas/genéticaRESUMEN
BACKGROUND: The seasonal epidemic of Kawasaki disease (KD) in winter in Japan suggests that low vitamin D status may affect KD through the immune system. We aimed to evaluate the effect of vitamin D on the onset and clinical course of KD. METHODS: We conducted a case-control study to compare 25-hydroxyvitamin D (25(OH)D) levels in KD patients admitted to our hospital between March 2018 and June 2021, with those in healthy controls from published Japanese data. In patients with KD, we evaluated the association of 25(OH)D levels with intravenous immunoglobulin resistance and coronary artery lesions. RESULTS: We compared 290 controls and 86 age-group-adjusted patients with KD. The 25(OH)D levels in KD patients were lower than those in the controls (median: 17 vs. 29 ng/mL, P < 0.001). In winter, 25(OH)D levels in KD patients were lower than those in summer (median: 13 vs. 19 ng/mL). The adjusted odds ratios for the onset of KD were 4.9 (95% CI: 2.5-9.6) for vitamin D insufficiency (25(OH)D: 12-20 ng/mL) and 29.4 (95% CI: 12.5-78.2) for vitamin D deficiency (25(OH)D < 12 ng/mL). Among 110 KD patients, 25(OH)D levels at diagnosis of KD were not associated with intravenous immunoglobulin resistance or coronary artery lesions. CONCLUSIONS: The 25(OH)D levels in patients with KD were lower than those in the controls, especially in winter. Lower 25(OH)D levels in winter were associated with an increased risk of KD onset. It remains to be elucidated whether the observed association has a causal relationship.
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Síndrome Mucocutáneo Linfonodular , Deficiencia de Vitamina D , Estudios de Casos y Controles , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/epidemiología , Estaciones del Año , Vitamina D , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/epidemiología , VitaminasRESUMEN
Reports on the treatment of bleeding associated with emicizumab administration are scarce. Herein, we report the case of an eight-year-old boy with moderate hemophilia A with an inhibitor who experienced tonsillar hemorrhage while undergoing emicizumab treatment. He visited our hospital for postprandial bloody vomiting. The activated partial thromboplastin time was 20.8 s; only a small amount of hemorrhage was observed in the retropharyngeal space, and tranexamic acid was administered. He experienced hematemesis on Day 2 of hospitalization, and fiberoptic laryngoscopy confirmed hemorrhage from the posterior tonsil. Varicose vessels were observed at the soft palate, and considering thrombosis, an emergency cauterization was performed instead of bypass therapy. In small children, observing the tonsils is difficult, and the coagulation ability of the patient with hemophilia A is inferior to that of healthy people, even under emicizumab administration. Thus, active hemorrhage assessment and appropriate hemostatic control are necessary.
RESUMEN
The quantitative antigen test based on the chemiluminescent enzyme immunoassay for SARS-CoV-2 has been used in international airports for quarantine in Japan. While cases of false-positive rapid antigen tests for SARS-CoV-2 were reported, false-positive cases of the quantitative antigen test with clinical information are rare. Here, we report a case of acute respiratory infection whose quantitative antigen test for SARS-CoV-2 was suspected to be false positive. A 9-month-old boy who presented with fever and rhinorrhea was admitted to our hospital under the Quarantine Act. He was diagnosed with COVID-19 based on the quantitative antigen test for SARS-CoV-2 performed at the quarantine station. None of the accompanying family members were positive for COVID-19. Nucleic acid amplification tests (NAAT) for SARS-CoV-2 were all negative, and multiplex polymerase chain reaction detected human rhinovirus or enterovirus infection. This case suggests that the results of the quantitative antigen test should be interpreted together with clinical information, and NAAT should be performed when false-positive results are suspected to avoid unnecessary isolation.
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COVID-19 , SARS-CoV-2 , Niño , Familia , Humanos , Pruebas Inmunológicas , Lactante , Masculino , Sensibilidad y EspecificidadAsunto(s)
Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Preescolar , Terapia Combinada , Trasplante de Células Madre de Sangre del Cordón Umbilical , Exones/genética , Resultado Fatal , Femenino , Humanos , Células Madre Neoplásicas/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Microbacterium species are coryneform gram-positive rods that are widely distributed in the environment and have been recently recognized as rare pathogens in humans. However, information about the epidemiologic and clinical characteristics of Microbacterium species is scarce. We herein reported an 11-year-old girl with acute leukemia who was found to have catheter-related bloodstream infection in her neutropenic phase. Gram-positive bacilli repeatedly grew on the blood cultures and were later confirmed by 16S rRNA analysis as Microbacterium paraoxydans. A literature review found available clinical courses in 21 cases (7 pediatric cases) of Microbacterium spp. bacteremia. Our case and those in literature suggested that Microbacterium spp. bacteremia often occurs in patients with indwelling central venous catheters; the literature review further suggested that removal of central venous catheters is required in most cases and that 16S rRNA sequence was useful in identifying in detail the species of Microbacterium.
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Actinobacteria/aislamiento & purificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bacteriemia/diagnóstico , Infecciones Relacionadas con Catéteres/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Actinobacteria/genética , Actinobacteria/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bacteriemia/inmunología , Bacteriemia/microbiología , Infecciones Relacionadas con Catéteres/inmunología , Infecciones Relacionadas con Catéteres/microbiología , Cateterismo Venoso Central/efectos adversos , Cateterismo Venoso Central/instrumentación , Catéteres Venosos Centrales/efectos adversos , Niño , ADN Bacteriano/aislamiento & purificación , Femenino , Humanos , Huésped Inmunocomprometido , Microbacterium , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , ARN Ribosómico 16S/genéticaRESUMEN
Fanconi anemia is a rare recessive disease characterized by multiple congenital abnormalities, progressive bone marrow failure, and a predisposition to malignancies. It results from mutations in one of the 22 known FANC genes. The number of Japanese Fanconi anemia patients with a defined genetic diagnosis was relatively limited. In this study, we reveal the genetic subtyping and the characteristics of mutated FANC genes in Japan and clarify the genotype-phenotype correlations. We studied 117 Japanese patients and successfully subtyped 97% of the cases. FANCA and FANCG pathogenic variants accounted for the disease in 58% and 25% of Fanconi anemia patients, respectively. We identified one FANCA and two FANCG hot spot mutations, which are found at low percentages (0.04-0.1%) in the whole-genome reference panel of 3,554 Japanese individuals (Tohoku Medical Megabank). FANCB was the third most common complementation group and only one FANCC case was identified in our series. Based on the data from the Tohoku Medical Megabank, we estimate that approximately 2.6% of Japanese are carriers of disease-causing FANC gene variants, excluding missense mutations. This is the largest series of subtyped Japanese Fanconi anemia patients to date and the results will be useful for future clinical management.
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Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Mutación , Anemia de Fanconi/epidemiología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Japón/epidemiología , MasculinoRESUMEN
To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography-mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2 and PKD1L2, were identified. SLC7A2 was associated with the plasma levels of arginine and ornithine, and PKD1L2 with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1 gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.
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Aminoácidos/sangre , Biomarcadores/sangre , Estudio de Asociación del Genoma Completo , Metabolómica , Adulto , Aminoácidos/genética , Femenino , Genoma Humano/genética , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic µ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.
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Ribonucleoproteínas Nucleares Heterogéneas , Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Translocación Genética , Adolescente , Niño , Supervivencia sin Enfermedad , Femenino , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Humanos , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Masculino , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Tasa de SupervivenciaRESUMEN
OBJECTIVE: AMP activated protein kinase (AMPK) is recognized as an important nutrient sensor contributing to regulation of cellular, tissue, and systemic metabolism. We aimed to identify specific amino acids which could modulate AMPK and determine effects on cellular and systemic metabolism. METHODS: We performed an unbiased amino acid screen to identify activators of AMPK. Detailed analysis of cellular signaling and metabolism was performed in cultured hepatoma cells, and in vivo glucose metabolism and metabolomic patterns were assessed in both chow-fed mice and mice made obese by high-fat diet feeding. RESULTS: Alanine acutely activates AMP kinase in both cultured hepatic cells and in liver from mice treated in vivo with Ala. Oral alanine administration improves systemic glucose tolerance in both chow and high fat diet fed mice, with reduced efficacy of Ala in mice with reduced AMPK activity. Our data indicate that Ala activation of AMPK is mediated by intracellular Ala metabolism, which reduces TCA cycle metabolites, increases AMP/ATP ratio, and activates NH3 generation. CONCLUSIONS: Ala may serve as a distinct amino acid energy sensor, providing a positive signal to activate the beneficial AMPK signaling pathway.
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Proteínas Quinasas Activadas por AMP/metabolismo , Alanina/farmacología , Glucosa/metabolismo , Hígado/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Aminoácidos/metabolismo , Animales , Metabolismo de los Hidratos de Carbono , Carcinoma Hepatocelular/metabolismo , Línea Celular , Dieta Alta en Grasa , Células Hep G2 , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , ObesidadRESUMEN
The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children's Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%, n = 916) than in those with T-ALL (71.9 ± 4.3%, n = 117, p < 0.001). In univariate analysis for BCP-ALL, children aged 1-6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/µL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%), ETV6-RUNX1 (97.4 ± 1.2%) or TCF3-PBX1 (96.9 ± 2.1%), and "Day8NoBlasts" (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.
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Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Análisis de Varianza , Pueblo Asiatico , Linfocitos B , Niño , Preescolar , Proteínas de Unión al ADN/genética , Diploidia , Femenino , Fusión Génica , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Tasa de Supervivencia , Linfocitos T , Tokio , Factor de Transcripción 4/genética , Resultado del Tratamiento , Proteína ETS de Variante de Translocación 6RESUMEN
Muscle biology is important topic in diabetes research. We have reported that a diet with ketogenic amino acids rich replacement (KAAR) ameliorated high-fat diet (HFD)-induced hepatosteatosis via activation of the autophagy system. Here, we found that a KAAR ameliorated the mitochondrial morphological alterations and associated mitochondrial dysfunction induced by an HFD through induction of the AKT/4EBP1 and autophagy signaling pathways in both fast and slow muscles. The mice were fed with a standard HFD (30% fat in food) or an HFD with KAAR (HFDKAAR). In both the gastrocnemius and the soleus, HFDKAAR ameliorated HFD-impaired mitochondrial morphology and mitochondrial function, characterized by decreased mitofusin 2, optic atrophy 1, peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α and PPARα levels and increased dynamin-related protein 1 levels. The decreased levels of phosphorylated AKT and 4EBP1 in the gastrocnemius and soleus of HFD-fed mice were remediated by HFDKAAR. Furthermore, the HFDKAAR ameliorated the HFD-induced autophagy defects in the gastrocnemius and soleus. These findings suggest that KAAR may be a novel strategy to combat obesity-induced mitochondrial dysfunction, likely through induction of the AKT/4EBP1 and autophagy pathways in skeletal muscle.
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Aminoácidos/farmacología , Autofagia/fisiología , Proteínas Portadoras/fisiología , Dieta Cetogénica , Mitocondrias/fisiología , Músculo Esquelético/fisiología , Obesidad/dietoterapia , Fosfoproteínas/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Transducción de Señal/fisiología , Proteínas Adaptadoras Transductoras de Señales , Aminoácidos/administración & dosificación , Animales , Autofagia/efectos de los fármacos , Sangre , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Proteínas de Ciclo Celular , Factores Eucarióticos de Iniciación , Homeostasis , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Obesidad/fisiopatología , Tamaño de los Órganos/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0-19 years) previously enrolled onto a Tokyo Children's Cancer Study Group trial were collected during 2013-2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10-17) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10-4) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10-6). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.
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Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Niño , Preescolar , Proteínas de Unión al ADN/genética , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Factor de Transcripción Ikaros/genética , Lactante , Recién Nacido , Japón , Desequilibrio de Ligamiento , Masculino , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Adulto JovenRESUMEN
BACKGROUND: Decreased circulating tryptophan (Trp) levels are frequently observed in elderly patients with neurodegenerative disease including Alzheimer's disease. Trp may serve as a potential biomarker for monitoring disease risk in elderly people. We aimed to investigate the association between low plasma Trp levels and olfactory function, which is known to predict age-related diseases including dementia in elderly people. METHODS: A total of 144 healthy elderly Japanese community (≥ 65 years old) dwellers from the Health, Aging and Nutritional Improvement study (HANI study) were the subjects of our analysis. Low Trp levels were classified using the lower limit values of the reference interval according to a previous report. Olfactory function was assessed using a card-type test called Open Essence, which includes 12 odour items that are familiar to Japanese people. The elderly subjects with low circulating Trp levels were compared to a control group with normal plasma Trp levels. RESULTS: We conducted the analyses using 144 people aged 65 years or older (mean age 73.7 ± 5.5 years; 36.1% men). The subjects showed normal serum albumin levels (4.4 ± 0.2 g/dL) and no daily living disabilities. Low plasma Trp levels (low Trp group) were found in 11.1% of the study population. The low Trp group showed a significantly lower correct-answer rate for the items india ink, perfume, curry and sweaty smelling socks than control group (P < 0.05). There was also a significant association between low Trp levels and low olfactory ability, after adjusting for age and sex. CONCLUSIONS: Lower plasma Trp levels were associated with a decrease in olfactory function in functionally competent older individuals. Because olfactory dysfunction predicts age-related diseases, low plasma Trp levels may represent a clinical sign of disease risk in elderly people.